Oxime compounds as agonists of the muscarinic m1 and/or m4 receptor

ABSTRACT

This invention relates to compounds that are agonists of the muscarinic M1 and/or M4 receptor and which are useful in the treatment of diseases mediated by the muscarinic M1 and M4 receptors. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula (I) where p; q; X 1; Y; R1; R2; R3; R4; R5 and R6 are as defined herein.

This invention relates to a class of novel oxime compounds, their salts,pharmaceutical compositions containing them and their use in therapy ofthe human body. In particular, the invention is directed to a class ofcompounds, which are agonists of the muscarinic M₁ and/or M₄ receptors,and hence are useful in the treatment of Alzheimer's disease,schizophrenia, cognitive disorders and other diseases mediated by themuscarinic M₁/M₄ receptors, as well as the treatment or alleviation ofpain.

BACKGROUND OF THE INVENTION

Muscarinic acetylcholine receptors (mAChRs) are members of the Gprotein-coupled receptor superfamily which mediate the actions of theneurotransmitter acetylcholine in both the central and peripheralnervous system. Five mAChR subtypes have been cloned, M₁ to M₅. The M₁mAChR is predominantly expressed post-synaptically in the cortex,hippocampus, striatum and thalamus; M₂ mAChRs are located predominantlyin the brainstem and thalamus, though also in the cortex, hippocampusand striatum where they reside on cholinergic synaptic terminals(Langmead et al., 2008 Br J Pharmacol). However, M₂ mAChRs are alsoexpressed peripherally on cardiac tissue (where they mediate the vagalinnervation of the heart) and in smooth muscle and exocrine glands. M₃mAChRs are expressed at relatively low level in the CNS but are widelyexpressed in smooth muscle and glandular tissues such as sweat andsalivary glands (Langmead et al., 2008 Br J Pharmacol).

Muscarinic receptors in the central nervous system, especially the M₁mAChR, play a critical role in mediating higher cognitive processing.Diseases associated with cognitive impairments, such as Alzheimer'sdisease, are accompanied by loss of cholinergic neurons in the basalforebrain (VVhitehouse et al., 1982 Science). In schizophrenia, which isalso characterised by cognitive impairments, mAChR density is reduced inthe pre-frontal cortex, hippocampus and caudate putamen of schizophrenicsubjects (Dean et al., 2002 Mol Psychiatry). Furthermore, in animalmodels, blockade or lesion of central cholinergic pathways results inprofound cognitive deficits and non-selective mAChR antagonists havebeen shown to induce psychotomimetic effects in psychiatric patients.Cholinergic replacement therapy has largely been based on the use ofacetylcholinesterase inhibitors to prevent the breakdown of endogenousacetylcholine. These compounds have shown efficacy versus symptomaticcognitive decline in the clinic, but give rise to dose-limiting sideeffects resulting from stimulation of peripheral M₂ and M₃ mAChRsincluding disturbed gastrointestinal motility, bradycardia, nausea andvomiting (http://www.drugs.com/pro/donepezil.html;http://www.drugs.com/pro/rivastigmine.html).

Further discovery efforts have targeted the identification of direct M₁mAChR agonists to target increases in cognitive function. Such effortsresulted in the identification of a range of agonists, exemplified bycompounds such as xanomeline, AF267B, sabcomeline, milameline andcevimeline. Many of these compounds have been shown to be highlyeffective in pre-clinical models of cognition in both rodents and/ornon-human primates. Milameline has shown efficacy versusscopolamine-induced deficits in working and spatial memory in rodents;sabcomeline displayed efficacy in a visual object discrimination task inmarmosets and xanomeline reversed mAChR antagonist-induced deficits incognitive performance in a passive avoidance paradigm.

Alzheimer's disease (AD) is the most common neurodegenerative disorder(26.6 million people worldwide in 2006) that affects the elderly,resulting in profound memory loss and cognitive dysfunction. Theaetiology of the disease is complex, but is characterised by twohallmark brain sequelae: aggregates of amyloid plaques, largely composedof amyloid-β peptide (Aβ), and neurofibrillary tangles, formed byhyperphosphorylated tau proteins. The accumulation of AR is thought tobe the central feature in the progression of AD and, as such, manyputative therapies for the treatment of AD are currently targetinginhibition of AR production. AR is derived from proteolytic cleavage ofthe membrane bound amyloid precursor protein (APP). APP is processed bytwo routes, non-amyloidgenic and amyloidgenic. Cleavage of APP byγ-secretase is common to both pathways, but in the former APP is cleavedby an α-secretase to yield soluble APPα. The cleavage site is within theAR sequence, thereby precluding its formation. However, in theamyloidgenic route, APP is cleaved by β-secretase to yield soluble APPβand also Aβ. In vitro studies have shown that mAChR agonists can promotethe processing of APP toward the soluble, non-amyloidogenic pathway. Invivo studies showed that the mAChR agonist, AF267B, altered disease-likepathology in the 3× TgAD transgenic mouse, a model of the differentcomponents of Alzheimer's disease (Caccamo et al., 2006 Neuron).Finally, the mAChR agonist cevimeline has been shown to give a small,but significant, reduction in cerebrospinal fluid levels of AR inAlzheimer's patients, thus demonstrating potential disease modifyingefficacy (Nitsch et al., 2000 Neurol).

Furthermore, preclinical studies have suggested that mAChR agonistsdisplay an atypical antipsychotic-like profile in a range ofpre-clinical paradigms. The mAChR agonist, xanomeline, reverses a numberof dopamine driven behaviours, including amphetamine induced locomotionin rats, apomorphine induced climbing in mice, dopamine agonist driventurning in unilateral 6-OH-DA lesioned rats and amphetamine inducedmotor unrest in monkeys (without EPS liability). It also has been shownto inhibit A10, but not A9, dopamine cell firing and conditionedavoidance and induces c-fos expression in prefrontal cortex and nucleusaccumbens, but not in striatum in rats. These data are all suggestive ofan atypical antipsychotic-like profile (Mirza et al., 1999 CNS DrugRev). Muscarinic receptors have also been implicated in the neurobiologyof addicition. The reinforcing effects of cocaine and other addictivesubstances are mediated by the mesolimbic dopamine system wherebehavioral and neurochemical studies have shown that the cholinergicmuscarinic receptor subtypes play important roles in regulation ofdopaminergic neurotransmission. For example M(4) (-/-) mice demonstratedsignificantly enhanced reward driven behaviour as result of exposure tococaine (Schmidt et al Psychopharmacology (2011) Aug;216(3): 367-78).Furthermore xanomeline has been dmoenstrated to block the effects ofcocaine in these models.

Xanomeline, sabcomeline, milameline and cevimeline have all progressedinto various stages of clinical development for the treatment ofAlzheimer's disease and/or schizophrenia. Phase II clinical studies withxanomeline demonstrated its efficacy versus various cognitive symptomdomains, including behavioural disturbances and hallucinationsassociated with Alzheimer's disease (Bodick et al., 1997 Arch Neurol).This compound was also assessed in a small Phase II study ofschizophrenics and gave a significant reduction in positive and negativesymptoms when compared to placebo control (Shekhar et al., 2008 Am JPsych). However, in all clinical studies xanomeline and other relatedmAChR agonists have displayed an unacceptable safety margin with respectto cholinergic side effects, including nausea, gastrointestinal pain,diarrhea, diaphoresis (excessive sweating), hypersalivation (excessivesalivation), syncope and bradycardia.

Muscarinic receptors are involved in central and peripheral pain. Paincan be divided into three different types: acute, inflammatory, andneuropathic. Acute pain serves an important protective function inkeeping the organism safe from stimuli that may produce tissue damagehowever management of post-surgical pain is required. Inflammatory painmay occur for many reasons including tissue damage, autoimmune response,and pathogen invasion and is triggered by the action of inflammatorymediators such as neuropeptides and prostaglandins which result inneuronal inflammation and pain. Neuropathic pain is associated withabnormal painful sensations to non-painful stimuli. Neuropathic pain isassociated with a number of different diseases/traumas such as spinalcord injury, multiple sclerosis, diabetes (diabetic neuropathy), viralinfection (such as HIV or Herpes). It is also common in cancer both as aresult of the disease or a side effect of chemotherapy. Activation ofmuscarinic receptors has been shown to be analgesic across a number ofpain states through the activation of receptors in the spinal cord andhigher pain centres in the brain. Increasing endogenous levels ofacetylcholine through acetylcholinesterase inhibitors, direct activationof muscarinic receptors with agonists or allosteric modulators has beenshown to have analgesic activity. In contrast blockade of muscarinicreceptors with antagonists or using knockout mice increases painsensitivity. Evidence for the role of the M₁ receptor in pain isreviewed by D. F. Fiorino and M. Garcia-Guzman, 2012.

More recently, a small number of compounds have been identified whichdisplay improved selectivity for the M₁ mAChR subtype over theperipherally expressed mAChR subtypes (Bridges et al., 2008 Bioorg MedChem Lett; Johnson et al., 2010 Bioorg Med Chem Lett; Budzik et al.,2010 ACS Med Chem Lett). Despite increased levels of selectivity versusthe M₃ mAChR subtype, some of these compounds retain significant agonistactivity at both this subtype and the M₂ mAChR subtype. Herein wedescribe a series of compounds which unexpectedly display high levels ofselectivity for the M₁ and/or M₄ mAChR over the M₂ and M₃ receptorsubtypes.

The Invention

The present invention provides compounds having activity as muscarinicM₁ and/or M₄ receptor agonists. More particularly, the inventionprovides compounds that exhibit selectivity for the M₁ or M₄ receptorrelative to the M₂ and M₃ receptor subtypes.

Accordingly, in a first embodiment (Embodiment 1.1), the inventionprovides a compound of the formula (1):

-   -   or a salt thereof, wherein:    -   p is 0, 1 or 2;    -   q is 0, 1 or 2;    -   Y is N, O, S or C;    -   X¹ and X² are saturated hydrocarbon groups which together        contain a total of four to nine carbon atoms and which link        together such that the moiety:

-   -   forms a mono or bicyclic ring system;    -   R¹ is a C₁₋₆ non-aromatic hydrocarbon group which is optionally        substituted with one to six fluorine atoms and wherein one or        two, but not all, carbon atoms of the hydrocarbon group may        optionally be replaced by a heteroatom selected from O, N and S        and oxidised forms thereof;    -   R² is cyano or a C₁₋₆ non-aromatic hydrocarbon group which is        optionally substituted with one to six fluorine atoms and        wherein one or two, but not all, carbon atoms of the hydrocarbon        group may optionally be replaced by a heteroatom selected from        O, N and S and oxidised forms thereof;    -   R³ is selected from hydrogen; halogen; cyano; hydroxy;        C₁₋₃alkoxy; and a C₁₋₅ non-aromatic hydrocarbon group which is        optionally substituted with one to six fluorine atoms and        wherein one or two, but not all, carbon atoms of the hydrocarbon        group may optionally be replaced by a heteroatom selected from        O, N and S and oxidized forms thereof;    -   R⁴ is a H or a C₁₋₆ non-aromatic hydrocarbon group which is        optionally substituted with one to six fluorine atoms and        wherein one or two, but not all, carbon atoms of the hydrocarbon        group may optionally be replaced by a heteroatom selected from        O, N and S and oxidised forms thereof;

R⁵ is fluorine; and

-   -   R⁶ is fluorine.

1.2 A compound according to Embodiment 1.1 wherein R¹ is a C₁₋₆non-aromatic hydrocarbon group containing 0, 1 or 2 carbon-carbonmultiple bonds, wherein the hydrocarbon group is optionally substitutedwith one to six fluorine atoms and wherein one or two, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidised forms thereof.

1.3 A compound according to either of Embodiments 1.1 and 1.2 wherein R¹is selected from C₁₋₆ alkyl; C₂₋₅ alkenyl; C₂₋₆ alkynyl; and C₁₋₆non-aromatic hydrocarbon groups consisting of or containing a C₃₋₆cycloalkyl or C₅₋₆ cycloalkenyl group; each of the said alkyl, alkenyl,alkynyl and non-aromatic hydrocarbon groups being optionally substitutedwith one to six fluorine atoms and wherein one or two, but not all,carbon atoms of each of the alkyl, alkenyl, alkynyl and non-aromatichydrocarbon groups may optionally be replaced by a heteroatom selectedfrom O, N and S and oxidised forms thereof.

1.4 A compound according to any one of Embodiments 1.1 to 1.3 wherein R¹is C₁₋₄ alkyl.

1.5 A compound according to Embodiment 1.4 wherein R¹ is selected from:

-   -   methyl    -   ethyl;    -   propyl;    -   isopropyl;    -   butyl.

1.6 A compound according to any one of Embodiments 1.1 to 1.5 wherein R²is selected from cyano; C₁₋₆ alkyl; C₂₋₅ alkenyl; C₂₋₆ alkynyl; and C₁₋₆non-aromatic hydrocarbon groups consisting of or containing a C₃₋₆cycloalkyl or C₅₋₆ cycloalkenyl group; each of the said alkyl, alkenyl,alkynyl and non-aromatic hydrocarbon groups being optionally substitutedwith one to six fluorine atoms and wherein one or two, but not all,carbon atoms of each of the alkyl, alkenyl, alkynyl and non-aromatichydrocarbon groups may optionally be replaced by a heteroatom selectedfrom O, N and S and oxidised forms thereof.

1.7 A compound according to any one of Embodiments 1.1 to 1.6 wherein R²is C₁₋₄ alkyl.

1.8 A compound according to Embodiment 1.7 wherein R² is selected from:

-   -   methyl    -   ethyl;    -   propyl;    -   isopropyl;    -   butyl. 1.9 A compound according to Embodiments 1.1 to 1.8        wherein R¹ and R² are independently methyl, ethyl, propyl or        isopropyl.

1.10 A compound according to Embodiment 1.1 wherein R³ is H ora C₁₋₆non-aromatic hydrocarbon group containing 0, 1 or 2 carbon-carbonmultiple bonds, wherein the hydrocarbon group is optionally substitutedwith one to six fluorine atoms and wherein one or two, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidised forms thereof.

1.11 A compound according to either of Embodiment 1,10 wherein R³ isselected from H; C₁₋₆ alkyl; C₂₋₅ alkenyl; C₂₋₆ alkynyl; and C₁₋₆non-aromatic hydrocarbon groups consisting of or containing a C₃₋₆cycloalkyl or C₅₋₆ cycloalkenyl group; each of the said alkyl, alkenyl,alkynyl and non-aromatic hydrocarbon groups being optionally substitutedwith one to six fluorine atoms and wherein one or two, but not all,carbon atoms of each of the alkyl, alkenyl, alkynyl and non-aromatichydrocarbon groups may optionally be replaced by a heteroatom selectedfrom O, N and S and oxidised forms thereof.

1.12 A compound according to any one of Embodiments 1.1 to 1.11 whereinR³ is selected from hydrogen, halogen, cyano, hydroxy, C₁₋₃ alkoxy andC₁₋₄ alkyl.

1.13 A compound according to Embodiment 1.12 wherein R³ is selected fromhydrogen, fluorine, methyl and methoxy.

1.14 A compound according to Embodiment 1.13 wherein R³ is selected fromhydrogen, fluorine and methoxy.

1.15 A compound according to Embodiment 1.14 wherein R³ is selected fromhydrogen and fluorine.

1.16 A compound according to Embodiment 1.15 wherein R³ is hydrogen.1.17 A compound according to Embodiment 1.16 wherein R³ is fluorine.

1.18 A compound according to any one of Embodiments 1.1 to 1.17 whereinR⁴ is H or an acyclic C₁₋₄ hydrocarbon group optionally substituted withone or more fluorine atoms.

1.19 A compound according to Embodiment 1.18 wherein R⁴ is H or anacyclic C₁₋₃ hydrocarbon group optionally substituted with one or morefluorine atoms.

1.20 A compound according to Embodiment 1.19 wherein R⁴ is H or a C₁₋₃alkyl group or a C₁₋₂ alkynyl group.

1.21 A compound according to Embodiment 1.20 wherein R⁴ is selected fromH, methyl, fluoromethyl, ethyl, ethynyl and 1-propynyl.

1.22 A compound according to Embodiment 1.21 wherein R⁴ is methyl.

1.23 A compound according to Embodiment 1.21 wherein R⁴ is H.

1.24 A compound according to any one of Embodiments 1.1 to 1.23 whereinp is 0 or 1.

1.25 A compound according to Embodiment 1.35 wherein p is 0.

1.26 A compound according to Embodiment 1.35 wherein p is 1.

1.27 A compound according to any one of Embodiments 1.1 to 1.26 whereinq is 0 or 1.

1.28 A compound according to Embodiment 1.27 wherein q is 0.

1.29 A compound according to Embodiment 1.27 wherein q is 1.

1.30 A compound according to any one of Embodiments 1.1 to 1.29 whereinY is N, O or CH₂.

1.31 A compound according to Embodiment 1.30 wherein Y is N.

1.32 A compound according to Embodiment 1.30 wherein Y is O.

1.33 A compound according to Embodiment 1.30 wherein Y is S.

1.34 A compound according to any one of Embodiments 1.1 to 1.33 whereinthe bicyclic ring system formed by the moiety:

is selected from:

-   -   (a) piperidine;    -   (b) azepane;    -   (a) an azabicyclo-octane or azabicyclo-nonane ring system;    -   (b) a 2-aza-spiro[3.4]octane or a 6-aza-spiro[3.4]octane ring        system; and    -   (c) a cyclopentanopyrrolidine ring system.

1.34 A compound according to any one of Embodiments 1.1 to 1.33 whereinX¹ and X² together contain four to seven carbon atoms.

1.35 A compound according to any one of Embodiments 1.1 to 1.34 whereinthe bicyclic ring system formed by the moiety:

is a bridged bicyclic ring system.

1.36 A compound according to Embodiment 1.35 wherein the bridgedbicyclic ring system is an azabicyclo-octane or azabicyclo-nonane ringsystem.

1.37 A compound according to Embodiment 1.36 wherein the bridgedbicyclic ring system is selected from an 8-aza-bicyclo[3.2.1]octane ringsystem, a 9-aza-bicyclo[3.3.1]nonane ring system and a6-aza-bicyclo[3.2.1]octane ring system.

1.38 A compound according to any one of Embodiments 1.1 to 1.34 whereinthe bicyclic ring system formed by the moiety:

is a spirocyclic ring system.

1.39 A compound according to Embodiment 1.38 wherein the spirocyclicring system is a 2-aza-spiro[3.4]octane or a 6-aza-spiro[3.4]octane ringsystem.

1.40 A compound according to any one of Embodiments 1.1 to 1.34 whereinthe bicyclic ring system formed by the moiety:

is a fused bicyclic ring system.

1.41 A compound according to Embodiment 1.40 wherein the fused bicyclicring system is a cyclopentanopyrrolidine ring system.

1.42 A compound according to any one of Embodiments 1.1 to 1.41 whereinthe bicyclic ring system formed by the moiety:

is selected from ring systems below:

1.43 A compound according to Embodiment 1.1 having the formula (2):

wherein R¹, R², R³, R⁴, R⁵, Y and p are as defined in any one ofEmbodiments 1.1 to 1.34; s is 0 or 1 and t is 0 or 1.

1.44 A compound according to Embodiment 1.43 wherein the total of s andt is 1.

1.45 A compound according to Embodiment 1.44 wherein s is 0 and t is 1.

1.46 A compound according to Embodiment 1.44 wherein s is 1 and t is 0.

1.47 A compound according to Embodiment 1.1 having the formula (3):

wherein R¹, R², R³, R⁴, R⁵, Y and p are as defined in any one ofEmbodiments 1.1 to 1.34; q is 1, 2 or 3 and r is 0 or 1, provided thatthe total of q and r is 2 or 3.

1.48 A compound according to Embodiment 1.47 wherein (i) r is 0 and q is2; (ii) r is 0 and q is 3; or (iii) r is 1 and q is 1.

1.49 A compound according to Embodiment 1.1 having the formula (4):

wherein R¹, R², R³, R⁴, R⁵, Y and p are as defined in any one ofEmbodiments 1.1 to 1.34; and u, v, w and x are each 0, 1 or 2 providedthat the total u+v+w+x is at least 1 and does not exceed 5.

1.50 A compound according to Embodiment 1.49 wherein each of u, v, w andx is 1.

1.51 A compound according to Embodiment 1.1 which is as defined in anyone of Examples 1-1 to 4-1.

1.52 A compound according to any one of Embodiments 1.1 to 1.50 having amolecular weight of less than 550, for example less than 500, or lessthan 450.

1.53 A compound according to any one of Embodiments 1.1 to 1.52 which isin the form of a salt.

1.54 A compound according to Embodiment 1.53 wherein the salt is an acidaddition salt.

1.55 A compound according to Embodiment 1.53 or Embodiment 1.54 whereinthe salt is a pharmaceutically acceptable salt.

Definitions

In this application, the following definitions apply, unless indicatedotherwise.

The term “treatment”, in relation to the uses of the compounds of theformulas (1) to (4), is used to describe any form of intervention wherea compound is administered to a subject suffering from, or at risk ofsuffering from, or potentially at risk of suffering from the disease ordisorder in question. Thus, the term “treatment” covers bothpreventative (prophylactic) treatment and treatment where measurable ordetectable symptoms of the disease or disorder are being displayed.

The term “effective therapeutic amount” as used herein (for example inrelation to methods of treatment of a disease or condition) refers to anamount of the compound which is effective to produce a desiredtherapeutic effect. For example, if the condition is pain, then theeffective therapeutic amount is an amount sufficient to provide adesired level of pain relief. The desired level of pain relief may be,for example, complete removal of the pain or a reduction in the severityof the pain.

The term “non-aromatic hydrocarbon group” (as in “C₁₋₅ non-aromatichydrocarbon group” or “acyclic C₁₋₅ non-aromatic hydrocarbon group”refers to a group consisting of carbon and hydrogen atoms and whichcontains no aromatic rings. The hydrocarbon group may be fully saturatedor may contain one or more carbon-carbon double bonds or carbon-carbontriple bonds, or mixtures of double and triple bonds. The hydrocarbongroup may be a straight chain or branched chain group or may consist ofor contain a cyclic group. Thus the term non-aromatic hydrocarbonincludes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenyl alkyl and so on.

The terms “alkyl”, “alkenyl”, “alkynyl”, “cycloalkyl” and “cycloalkenyl”are used in their conventional sense (e.g. as defined in the IUPAC GoldBook) unless indicated otherwise.

The term “cycloalkyl” as used herein, where the specified number ofcarbon atoms permits, includes both monocyclic cycloalkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, andbicyclic and tricyclic groups. Bicyclic cycloalkyl groups includebridged ring systems such as bicycloheptane, bicyclooctane andadamantane.

In the definitions of R¹, R², R³ and R⁴ above, where stated, one or twobut not all, carbon atoms of the non-aromatic hydrocarbon group mayoptionally be replaced by a heteroatom selected from O, N and S andoxidised forms thereof. It will be appreciated that when a carbon atomis replaced by a heteroatom, the lower valencies of the heteroatomscompared to carbon means that fewer atoms will be bonded to theheteroatoms than would have been bonded to the carbon atom that has beenreplaced. Thus, for example, replacement of a carbon atom (valency offour) in a CH₂ group by oxygen (valency of two) will mean that theresulting molecule will contain two less hydrogen atoms and replacementof a carbon atom (valency of four) in a CH₂ group by nitrogen (valencyof three) will mean that the resulting molecule will contain one lesshydrogen atom.

Examples of a heteroatom replacements for carbon atoms includereplacement of a carbon atom in a —CH₂-CH₂—CH₂— chain with oxygen orsulfur to give an ether —CH₂—O—CH₂— or thioether —CH₂—S—CH₂—,replacement of a carbon atom in a group CH₂—C≡C—H with nitrogen to givea nitrile (cyano) group CH₂—C≡N, replacement of a carbon atom in a group—CH₂—CH₂—CH₂— with C═O to give a ketone —CH₂—C(O)—CH₂—, replacement of acarbon atom in a group —CH₂—CH₂—CH₂— with S═O or SO₂ to give a sulfoxide—CH₂—S(O)—CH₂— or sulfone —CH₂—S(O)₂—CH₂—, replacement of a carbon atomin a —CH₂—CH₂—CH₂— chain with C(O)NH to give an amide —CH₂—CH₂—C(O)—NH—,replacement of a carbon atom in a —CH₂—CH₂—CH₂— chain with nitrogen togive an amine —CH₂—NH—CH₂—, and replacement of a carbon atom in a—CH₂—CH₂—CH₂— chain with C(O)O to give an ester (or carboxylic acid)—CH₂—CH₂—C(O)—O—. In each such replacement, at least one carbon atom ofthe hydrocarbon group must remain.

Salts

Many compounds of the formulas (1) to (4) can exist in the form ofsalts, for example acid addition salts or, in certain cases salts oforganic and inorganic bases such as carboxylate, sulfonate and phosphatesalts. All such salts are within the scope of this invention, andreferences to compounds of the formulas (1) to (4) include the saltforms of the compounds as defined in Embodiments 1.53 to 1.55.

The salts are typically acid addition salts.

The salts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods such as methods described in Pharmaceutical Salts: Properties,Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth(Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia such as ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are used.

Acid addition salts (as defined in Embodiment 1.54) may be formed with awide variety of acids, both inorganic and organic. Examples of acidaddition salts falling within Embodiment 1.54 include mono- or di-saltsformed with an acid selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric,ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic,fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic(e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric,glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric,hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic),lactobionic, maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic,methanesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic,salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric,tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic andvaleric acids, as well as acylated amino acids and cation exchangeresins.

Where the compounds of the formula (1) contain an amine function, thesemay form quaternary ammonium salts (Embodiment 1.72), for example byreaction with an alkylating agent according to methods well known to theskilled person. Such quaternary ammonium compounds are within the scopeof formula (1).

The compounds of the invention may exist as mono- or di-salts dependingupon the pKa of the acid from which the salt is formed.

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, saltsthat are not pharmaceutically acceptable may also be prepared asintermediate forms which may then be converted into pharmaceuticallyacceptable salts. Such non-pharmaceutically acceptable salts forms,which may be useful, for example, in the purification or separation ofthe compounds of the invention, also form part of the invention.

Stereoisomers

Stereoisomers are isomeric molecules that have the same molecularformula and sequence of bonded atoms but which differ only in thethree-dimensional orientations of their atoms in space. Thestereoisomers can be, for example, geometric isomers or optical isomers.

Geometric Isomers

With geometric isomers, the isomerism is due to the differentorientations of an atom or group about a double bond, as in cis andtrans (Z and E) isomerism about a carbon-carbon double bond, or cis andtrans isomers about an amide bond, or syn and anti isomerism about acarbon nitrogen double bond (e.g. in an oxime), or rotational isomerismabout a bond where there is restricted rotation, or cis and transisomerism about a ring such as a cycloalkane ring.

Accordingly, in another embodiment (Embodiment 1.73), the inventionprovides a geometric isomer of a compound according to any one ofEmbodiments 1.1 to 1.72.

Optical Isomers

Where compounds of the formula contain one or more chiral centres, andcan exist in the form of two or more optical isomers, references to thecompounds include all optical isomeric forms thereof (e.g. enantiomers,epimers and diastereoisomers), either as individual optical isomers, ormixtures (e.g. racemic mixtures) or two or more optical isomers, unlessthe context requires otherwise.

Accordingly, in another embodiment (Embodiment 1.74) the inventionprovides a compound according to any one of Embodiments 1.1 to 1.73which contains a chiral centre.

The optical isomers may be characterised and identified by their opticalactivity (i.e. as + and − isomers, or d and/isomers) or they may becharacterised in terms of their absolute stereochemistry using the “Rand S” nomenclature developed by Cahn, Ingold and Prelog, see AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, NewYork, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew.Chem. Int. Ed. Engl., 1966, 5, 385-415. Optical isomers can be separatedby a number of techniques including chiral chromatography(chromatography on a chiral support) and such techniques are well knownto the person skilled in the art. As an alternative to chiralchromatography, optical isomers can be separated by formingdiastereoisomeric salts with chiral acids such as (+)-tartaric acid,(−)-pyroglutamic acid, (−)-di-toluoyl-L-tartaric acid, (+)-mandelicacid, (−)-malic acid, and (−)-camphorsulphonic, separating thediastereoisomers by preferential crystallisation, and then dissociatingthe salts to give the individual enantiomer of the free base.

Where compounds of the invention exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers.

Accordingly, in another embodiment (Embodiment 1.75), the inventionprovides compositions containing a compound according to Embodiment 1.74having one or more chiral centres, wherein at least 55% (e.g. at least60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of Embodiment1.73 is present as a single optical isomer (e.g. enantiomer ordiastereoisomer).

In one general embodiment (Embodiment 1.76), 99% or more (e.g.substantially all) of the total amount of the compound (or compound foruse) of Embodiment 1.74 is present as a single optical isomer.

For example, in one embodiment (Embodiment 1.77) the compound is presentas a single enantiomer.

In another embodiment (Embodiment 1.78), the compound is present as asingle diastereoisomer.

The invention also provides mixtures of optical isomers, which may beracemic or non-racemic. Thus, the invention provides:

1.79 A compound according to Embodiment 1.74 which is in the form of aracemic mixture of optical isomers.

1.80 A compound according to Embodiment 1.74 which is in the form of anon-racemic mixture of optical isomers.

Isotopes

The compounds of the invention as defined in any one of Embodiments 1.1to 1.80 may contain one or more isotopic substitutions, and a referenceto a particular element includes within its scope all isotopes of theelement. For example, a reference to hydrogen includes within its scope¹ H, ²H (D), and ³H (T). Similarly, references to carbon and oxygeninclude within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and¹⁸O.

In an analogous manner, a reference to a particular functional groupalso includes within its scope isotopic variations, unless the contextindicates otherwise. For example, a reference to an alkyl group such asan ethyl group also covers variations in which one or more of thehydrogen atoms in the group is in the form of a deuterium or tritiumisotope, e.g. as in an ethyl group in which all five hydrogen atoms arein the deuterium isotopic form (a perdeuteroethyl group).

The isotopes may be radioactive or non-radioactive. In one embodiment ofthe invention (Embodiment 1.81), the compound of any one of Embodiments1.1 to 1.80 contains no radioactive isotopes. Such compounds arepreferred for therapeutic use. In another embodiment (Embodiment 1.82),however, the compound of any one of

Embodiments 1.1 to 1.80 may contain one or more radioisotopes. Compoundscontaining such radioisotopes may be useful in a diagnostic context.

Solvates

Compounds of the formula (1) as defined in any one of Embodiments 1.1 to1.82 may form solvates. Preferred solvates are solvates formed by theincorporation into the solid state structure (e.g. crystal structure) ofthe compounds of the invention of molecules of a non-toxicpharmaceutically acceptable solvent (referred to below as the solvatingsolvent). Examples of such solvents include water, alcohols (such asethanol, isopropanol and butanol) and dimethylsulfoxide. Solvates can beprepared by recrystallising the compounds of the invention with asolvent or mixture of solvents containing the solvating solvent. Whetheror not a solvate has been formed in any given instance can be determinedby subjecting crystals of the compound to analysis using well known andstandard techniques such as thermogravimetric analysis (TGE),differential scanning calorimetry (DSC) and X-ray crystallography. Thesolvates can be stoichiometric or non-stoichiometric solvates.Particularly preferred solvates are hydrates, and examples of hydratesinclude hemihydrates, monohydrates and dihydrates.

Accordingly, in further embodiments 1.83 and 1.84, the inventionprovides:

1.83 A compound according to any one of Embodiments 1.1 to 1.82 in theform of a solvate.

1.84 A compound according to Embodiment 1.83 wherein the solvate is ahydrate.

For a more detailed discussion of solvates and the methods used to makeand characterise them, see Bryn et al., Solid-State Chemistry of Drugs,Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA,1999, ISBN 0-967-06710-3.

Alternatively, rather than existing as a hydrate, the compound of theinvention may be anhydrous. Therefore, in another embodiment (Embodiment1.85), the invention provides a compound as defined in any one ofEmbodiments 1.1 to 1.83 in an anhydrous form (e.g. anhydrous crystallineform).

Crystalline and Amorphous Forms

The compounds of any one of Embodiments 1.1 to 1.83 may exist in acrystalline or non-crystalline (e.g. amorphous) state. Whether or not acompound exists in a crystalline state can readily be determined bystandard techniques such as X-ray powder diffraction (XRPD). Crystalsand their crystal structures can be characterised using a number oftechniques including single crystal X-ray crystallography, X-ray powderdiffraction (XRPD), differential scanning calorimetry (DSC) and infrared spectroscopy, e.g. Fourier Transform infra-red spectroscopy (FTIR).The behaviour of the crystals under conditions of varying humidity canbe analysed by gravimetric vapour sorption studies and also by XRPD.Determination of the crystal structure of a compound can be performed byX-ray crystallography which can be carried out according to conventionalmethods such as those described herein and as described in Fundamentalsof Crystallography, C. Giacovazzo, H. L. Monaco, D. Viterbo, F.Scordari, G. Gilli, G. Zanotti and M. Catti, (International Union ofCrystallography/Oxford University Press, 1992 ISBN 0-19-855578-4 (p/b),0-19-85579-2 (h/b)). This technique involves the analysis andinterpretation of the X-ray diffraction of single crystal. In anamorphous solid, the three dimensional structure that normally exists ina crystalline form does not exist and the positions of the moleculesrelative to one another in the amorphous form are essentially random,see for example Hancock et al. J. Pharm. Sci. (1997), 86, 1).

Accordingly, in further embodiments, the invention provides:

1.86 A compound according to any one of Embodiments 1.1 to 1.85 in acrystalline form.

1.80 A compound according to any one of Embodiments 1.1 to 1.85 whichis:

(a) from 50% to 100% crystalline, and more particularly is at least 50%crystalline, or at least 60% crystalline, or at least 70% crystalline,or at least 80% crystalline, or at least 90% crystalline, or at least95% crystalline, or at least 98% crystalline, or at least 99%crystalline, or at least 99.5% crystalline, or at least 99.9%crystalline, for example 100% crystalline.

1.88 A compound according to any one of Embodiments 1.1 to 1.85 which isin an amorphous form.

Prodrugs

The compounds of the formula (1) as defined in any one of Embodiments1.1 to 1.88 may be presented in the form of a pro-drug. By “prodrugs” ismeant for example any compound that is converted in vivo into abiologically active compound of the formula (1), as defined in any oneof Embodiments 1.1 to 1.88.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (-C(=O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyhydroxyl groups present in the parent compound with, where appropriate,prior protection of any other reactive groups present in the parentcompound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in ADEPT, GDEPT, LI DEPT, etc.).For example, the prodrug may be a sugar derivative or other glycosideconjugate, or may be an amino acid ester derivative.

Accordingly, in another embodiment (Embodiment 1.89), the inventionprovides a pro-drug of a compound as defined in any one of Embodiments1.1 to 1.82 wherein the compound contains a functional group which isconvertible under physiological conditions to form a hydroxyl group oramino group.

Complexes and clathrates

Also encompassed by formula (1) in Embodiments 1.1 to 1.89 are complexes(e.g. inclusion complexes or clathrates with compounds such ascyclodextrins, or complexes with metals) of the compounds of Embodiments1.1 to 1.89.

Accordingly, in another embodiment (Embodiment 1.90), the inventionprovides a compound according to any one of Embodiments 1.1 to 1.89 inthe form of a complex or clathrate.

Biological Activity and Therapeutic Uses

The compounds of the present invention have activity as muscarinic M₁and/or M₄ receptor agonists. The muscarinic activity of the compoundscan be determined using the Phospho-ERK1/2 assay described in Example Abelow.

A significant advantage of compounds of the invention is that they arehighly selective for the M₁ and/or M₄ receptors relative to the M₂ andM₃ receptor subtypes. Compounds of the invention are neither agonistsnor antagonists of the M₂ and M₃ receptor subtypes. For example, whereascompounds of the invention typically have pEC₅₀ values of at least 6(preferably at least 6.5) and E_(max) values of greater than 80(preferably greater than 95) against the M₁ and/or M₄ receptor in thefunctional assay described in Example A, they may have pEC₅₀ values ofless than 5 and E_(max) values of less than 20% when tested against theM₂ and M₃ subtypes in the functional assay of Example A.

Some compounds of the invention have activity at both the M₁ and M₄receptors, and some have activity at the M₄ receptor.

Accordingly, in Embodiments 2.1 to 2.15, the invention provides:

2.1 A compound according to any one of Embodiments 1.1 to 1.90 for usein medicine.

2.2 A compound according to any one of Embodiments 1.1 to 1.90 for useas a muscarinic M₁ and/or M₄ receptor agonist.

2.3 A compound according to any one of Embodiments 1.1 to 1.90 which isa muscarinic M₁ receptor agonist having a pEC₅₀ greater than 6.9 and anE_(max) of at least 80 against the M₁ receptor in the assay of Example Aherein or an assay substantially similar thereto.

2.4 A compound according to Embodiment 2.3 which is a muscarinic M₁receptor agonist having a pEC₅₀ greater than 7.0.

2.5 A compound according to Embodiment 2.3 or Embodiment 2.4 having anE_(max) of at least 90 against the M₁ receptor.

2.6 A compound according to any one of Embodiments 1.1 to 1.90 which isa muscarinic M₁ and M₄ receptor agonist having a pEC₅₀ in the range from6.0 to 7.8 and an E_(max) of at least 70 against the muscarinic M₁ andM₄ receptors in the assay of Example A herein or an assay substantiallysimilar thereto.

2.7 A compound according to any one of Embodiments 1.1 to 1.90 which isa muscarinic M₄ receptor agonist having a pEC₅₀ greater than 7.0.

2.8 A compound according to Embodiment 2.6 or Embodiment 2.7 having anE_(max) of at least 90 against the M₄ receptor.

2.9 A compound according to any one of Embodiments 1.1 to 1.90 which isa muscarinic M₄ receptor agonist having a pEC₅₀ in the range from 6.0 to7.8 and an E_(max) of at least 70 against the muscarinic M₄ receptor inthe assay of Example A herein or an assay substantially similar thereto.

2.10 A compound according to any one of Embodiments 2.3 to 2.9 which isselective for the M₁ and M₄ receptor compared to the muscarinic M₂ andM₃ receptors.

2.11 A compound according to Embodiment 2.9 which is selective for theM₄ receptor compared to the muscarinic M₂ and M₃ receptors.

2.12 A compound according to any one of Embodiments 2.3 to 2.5 which isselective for the M₁ receptor compared to the muscarinic M₂, M₃ and M₄receptors.

2.13 A compound according to any one of Embodiments 2.7 or 2.9 which isselective for the M₄ receptor compared to the muscarinic M₁, M₂ and M₃receptors. 2.14 A compound according to any one of Embodiments 2.3 to2.13 which has a pEC₅₀ of less than 5 and an E_(max) of less than 50against the muscarinic M₂ and M₃ receptor subtypes.

2.15 A compound according to Embodiment 2.14 which has a pEC₅₀ of lessthan 4.5 and/or an E_(max) of less than 30 against the muscarinic M₂ andM₃ receptor subtypes.

2.16 A compound according to any one of Embodiments 1.1 to 1.90 andEmbodiments 2.3 to 2.15 for use in the treatment of a disease orcondition mediated by the muscarinic M₁ and/or M₄ receptors.

By virtue of their muscarinic M₁ and/or M₄ receptor agonist activity,compounds of the invention can be used in the treatment of Alzheimer'sdisease, schizophrenia and other psychotic disorders, cognitivedisorders and other diseases mediated by the muscarinic M₁ and/or M₄receptor, and can also be used in the treatment of various types ofpain.

Accordingly, in Embodiments 2.17 to 2.38, the invention provides:

2.17 A compound according to any one of Embodiments 1.1 to 1.90 for usein the treatment of a cognitive disorder or psychotic disorder.

2.18 A compound for use in according to Embodiment 2.17 wherein thecognitive disorder or psychotic disorder comprises, arises from or isassociated with a condition selected from cognitive impairment, MildCognitive Impairment, frontotemporal dementia, vascular dementia,dementia with Lewy bodies, presenile dementia, senile dementia,Friederich's ataxia, Down's syndrome, Huntington's chorea, hyperkinesia,mania, Tourette's syndrome, Alzheimer's disease, progressivesupranuclear palsy, impairment of cognitive functions includingattention, orientation, learning disorders, memory (i.e. memorydisorders, amnesia, amnesic disorders, transient global amnesia syndromeand age-associated memory impairment) and language function; cognitiveimpairment as a result of stroke, Huntington's disease, Pick disease,Aids-related dementia or other dementia states such as multi-infarctdementia, alcoholic dementia, hypotiroidism-related dementia, anddementia associated to other degenerative disorders such as cerebellaratrophy and amyotropic lateral sclerosis; other acute or sub-acuteconditions that may cause cognitive decline such as delirium ordepression (pseudodementia states) trauma, head trauma, age relatedcognitive decline, stroke, neurodegeneration, drug-induced states,neurotoxic agents, age related cognitive impairment, autism relatedcognitive impairment, Down's syndrome, cognitive deficit related topsychosis, and post-electroconvulsive treatment related cognitivedisorders; cognitive disorders due to drug abuse or drug withdrawalincluding nicotine, cannabis, amphetamine, cocaine, Attention DeficitHyperactivity Disorder (ADHD) and dyskinetic disorders such asParkinson's disease, neuroleptic-induced parkinsonism, and tardivedyskinesias, schizophrenia, schizophreniform diseases, psychoticdepression, mania, acute mania, paranoid, hallucinogenic and delusionaldisorders, personality disorders, obsessive compulsive disorders,schizotypal disorders, delusional disorders, psychosis due tomalignancy, metabolic disorder, endocrine disease or narcolepsy,psychosis due to drug abuse or drug withdrawal, bipolar disorders andschizo-affective disorder.

2.19 A compound according to any one of Embodiments 1.1 to 1.90 for usein the treatment of Alzheimer's disease.

2.20 A compound according to any one of Embodiments 1.1 to 1.90 for usein the treatment of Schizophrenia.

2.21 A method of treatment of a cognitive disorder in a subject (e.g. amammalian patient such as a human, e.g. a human in need of suchtreatment), which method comprises the administration of atherapeutically effective dose of a compound according to any one ofEmbodiments 1.1 to 1.90.

2.22 A method according to Embodiment 2.21 wherein the cognitivedisorder comprises, arises from or is associated with a condition asdefined in Embodiment 2.18.

2.23 A method according to Embodiment 2.22 wherein the cognitivedisorder arises from or is associated with Alzheimer's disease.

2.24 A method according to Embodiment 2.22 wherein the cognitivedisorder is Schizophrenia.

2.25 The use of a compound according to any one of Embodiments 1.1 to1.90 for the manufacture of a medicament for the treatment of acognitive disorder.

2.26 The use according to Embodiment 2.25 wherein the cognitive disordercomprises, arises from or is associated with a condition as defined inEmbodiment 2.18.

2.27 The use according to Embodiment 2.26 wherein the cognitive disorderarises from or is associated with Alzheimer's disease.

2.28 The use according to Embodiment 2.26 wherein the cognitive disorderis Schizophrenia.

2.29 A compound according to any one of Embodiments 1.1 to 1.90 for thetreatment or lessening the severity of acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, visceral pain,osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

2.30 A method of treatment or lessening the severity of acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, or cancer pain, which method comprises theadministration of a therapeutically effective dose of a compoundaccording to any one of Embodiments 1.1 to 1.90.

2.31 A compound according to any one of Embodiments 1.1 to 1.90 for thetreatment of peripheral disorders such as reduction of intra ocularpressure in Glaucoma and treatment of dry eyes and dry mouth includingSjogren's Syndrome.

2.32 A method of treatment of peripheral disorders such as reduction ofintra ocular pressure in Glaucoma and treatment of dry eyes and drymouth including Sjogren's

Syndrome, which method comprises the administration of a therapeuticallyeffective dose of a compound according to any one of Embodiments 1.1 to1.90.

2.33 The use of a compound according to any one of Embodiments 1.1 to1.90 for the manufacture of a medicament for the treatment or lesseningthe severity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, visceral pain, osteoarthritis pain,postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica,back pain, head or neck pain, severe or intractable pain, nociceptivepain, breakthrough pain, postsurgical pain, or cancer pain or for thetreatment of peripheral disorders such as reduction of intra ocularpressure in Glaucoma and treatment of dry eyes and dry mouth includingSjogren's Syndrome.

2.34 The use of a compound according to any one of Embodiments 1.1 to1.90 for the use in the treatment of skin lesions for example due topemphigus vulgaris, dermatitis herpetiformis, pemphigoid and otherblistering skin conditions.

2.35 The use of a compound according to any one of Embodiments 1.1 to1.90 for the use in treating, preventing, ameliorating or reversingconditions associated with altered gastro-intestinal function andmotility such as functional dyspepsia, irritable bowel syndrome,gastroesophageal acid reflux (GER) and esophageal dysmotility, symptomsof gastroparesis and chronic diarrhea.

2.36 The use of a compound according to any one of Embodiments 1.1 to1.90 for the use in in the treatment of olfactory dysfunction such asBosma-Henkin-Christiansen syndrome, chemical poisoning (e.g. seleniumand silver), hypopituitarism, Kallmann Syndrome, skull fractures, tumourtherapy and underactive thyroid gland.

2.37 The use of a compound according to any one of Embodiments 1.1 to1.90 for the treatment of addiction.

2.38 The use of a compound according to any one of Embodiments 1.1 to1.90 for the treatment of movement disorders such as Parkinson'sdisease, ADHD, Huntingdon's disease, tourette's syndrome and othersyndromes associated with dopaminergic dysfunction as an underlyingpathogenetic factor driving disease.

Methods for the Preparation of Compounds of the Formula (1)

Compounds of the formula (1) can be prepared in accordance withsynthetic methods well known to the skilled person and as describedherein.

Accordingly, in another embodiment (Embodiment 3.1), the inventionprovides a process for the preparation of a compound as defined in anyone of Embodiments 1.1 to 1.90, which process comprises:

(A) the reaction of a compound of the formula (10)

with a compound of the formula (11):

under reductive amination conditions; wherein R¹, R², R³, R⁴, R⁵, R⁶,X¹, X², p and q are as defined in any one of Embodiments 1.1 to 1.90; or

(B) the reaction of a compound of the formula (12):

with a compound of the formula Cl—C(═O)—CH₂—R⁴, in the presence of abase; or

(C) the reaction of a compound of the formula (10)

with a compound of the formula (13):

under nucleophilic substitution conditions; wherein R¹, R², R³, R⁴, R⁵,R⁶, X¹, X², p and q are as defined in any one of Embodiments 1.1 to1.90; and optionally:

(D) the reaction of a compound of the formula (14):

with a compound of the formula NH₂OR¹; or

(E) the reaction of a compound of the formula (15):

with a compound of the formula NH₂R², in the presence of a base; or

(F) the reaction of a compound of the formula (15):

with a NaCN; or

(G) converting one compound of the formula (1) to another compound ofthe formula (1).

In process variant (A), the piperidine heterocycle (10) is reacted withthe substituted ketone (11) under reductive amination conditions. Thereductive amination reaction is typically carried out at ambienttemperature to mild heating (e.g. to a temperature of about 20° C. toabout 70° C.) using either a borohydride reducing agent such as sodiumtriacetoxy-borohydride in a solvent such as dichloromethane,dichloroethane or dimethylformamide containing acetic acid, or sodiumcyanoborohydride in combination with zinc chloride, or sodiumtriacetoxy-borohydride in combination with titanium isopropoxide.

Process variant (B) is typically carried out in an aprotic solvent suchas dichloromethane or dichloroethane in the presence of anon-interfering base such as triethylamine. The reaction may beconducted at room temperature.

In process variant (C), the piperidine heterocycle (10) is reacted withthe sulfonic ester (13, R=methyl, trifluoromethyl or 4-methylphenyl) ina nucleophilic substitution reaction which is typically carried out withmild heating (e.g. to a temperature of from about 40 ° C. to about 70°C.) either neat, with no solvent, or in a suitable solvent such astetrahydrofuran, acetonitrile or dimethylacetamide.

Process variant (D) is typically carried out in an protic solvent suchas methanol in the presence of a non-interfering base such as sodiumacetate. The reaction may be conducted at room temperature.

Process variant (E) is typically carried out in an aprotic solvent suchas dichloromethane, dichloroethane or dimethylformamide in the presenceof a non-interfering base such as potassium carbonate. The reaction istypically carried out at ambient temperature to moderate heating (e.g.to a temperature of about 20° C. to about 120° C.).

Process variant (F) is typically carried out in an aprotic solvent suchas DMSO or dimethylformamide. The reaction is typically carried out atambient temperature to moderate heating (e.g. to a temperature of about20° C. to about 120° C.).

Intermediate compounds of the formula (12) can be prepared by the seriesof reactions shown in Scheme 1 below.

In reaction Scheme 1, the piperidine (10) is reacted with theBoc-protected ketone (12) under reductive amination conditions. Thereductive amination reaction is typically carried out with mild heating(e.g. to a temperature of from about 40° C. to about 70° C.) in thepresence of either sodium cyanoborohydride in combination with zincchloride or sodium triacetoxyborohydride in combination with titaniumisopropoxide in a solvent such as dichloromethane or dichloroethanecontaining acetic acid to give an intermediate piperidine compound (17)which is then deprotected by removal of the

Boc group by treatment with acid (e.g. trifluoroacetic acid indichloromethane) to give the compound (12).

Compounds of the formula (14) can be prepared by the sequence ofreactions shown in Scheme 2 below.

In Scheme 2, the 4-cyanopiperidine derivative (18) is reacted with theketone (11) under reductive amination conditions of the type describedabove to give an intermediate 4-cyanopiperidine compound (19) whichundergoes selectively addition of a Grignard reagent to give the ketone(14).

Compounds of the formula (15) can also be prepared by the sequence ofreactions shown in Scheme 3 below.

In reaction Scheme 3, the piperidine ester (20, R″=ethyl or methyl) isreacted with the substituted ketone (13) under reductive aminationconditions of the type described above to give an intermediate estercompound (21) which is then selectively hydrolysed under mild conditionsusing lithium hydroxide or sodium hydroxide to give compound (22). Thecarboxylic acid (22) is reacted with the compound of formula NH₂OR¹under typical amide coupling conditions to give amide (23).The reactionmay be carried out in the presence of a reagent of the type commonlyused in the formation of amide bonds. Examples of such reagents include1,3-dicyclohexylcarbodiimide (DCC) (Sheehan et al, J. Amer. Chem Soc.1955, 77, 1067), 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide(referred to herein either as EDC or EDAC) (Sheehan et al, J. Org.Chem., 1961, 26, 2525), uronium-based coupling agents such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) and phosphonium-based coupling agents such as1-benzo-triazolyloxytris-(pyrrolidino)phosphonium hexafluorophosphate(PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205).Carbodiimide-based coupling agents are advantageously used incombination with 1-hydroxy-7-azabenzotriazole (HOAt) (L. A. Carpino, J.Amer. Chem. Soc., 1993, 115, 4397) or 1-hydroxybenzotriazole (HOBt)(Konig et al, Chem. Ber., 103, 708, 2024-2034). A preferred amidecoupling agent is HATU. The coupling reaction is typically carried outin a non-aqueous, non-protic solvent such as acetonitrile, dioxane,dimethylsulphoxide, dichloromethane, dimethylformamide orN-methylpyrrolidinone, or in an aqueous solvent optionally together withone or more miscible co-solvents. The reaction can be carried out atroom temperature or, where the reactants are less reactive at anappropriately elevated temperature, for example a temperature up toabout 100° C., e.g. 50-80° C. The reaction may optionally be carried outin the presence of a non-interfering base, for example a tertiary aminesuch as triethylamine or N,N-diisopropylethylamine. As an alternative, areactive derivative of the carboxylic acid, e.g. an anhydride or acidchloride, may be used. The acid chloride is typically reacted with thecompound of formula NH₂OR¹ in the presence of a base such as sodiumbicarbonate. The acid chloride can be prepared using standard methods,for example by treatment of the acid with oxalyl chloride in thepresence of a catalytic amount of dimethylformamide.

Treatment of amide (23) with a chlorinating agent, such as thionylchloride gives the N-alkoxypiperidine-4-carboximidoyl chloride (15).

Once formed, one compound of the formula (1), (2), (3) or (4), or aprotected derivative thereof, can be converted into another compound ofthe formula (1), (2), (3) or (4) by methods well known to the skilledperson. Examples of synthetic procedures for converting one functionalgroup into another functional group are set out in standard texts suchas Advanced Organic Chemistry and Organic Syntheses (see referencesabove) or Fiesers' Reagents for Organic Synthesis, Volumes 1-17, JohnWiley, edited by Mary Fieser (ISBN: 0-471-58283-2).

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Protective Groups in Organic Synthesis (T. Greene and P. Wuts; 3rdEdition; John Wiley and Sons, 1999).

Compounds made by the foregoing methods may be isolated and purified byany of a variety of methods well known to those skilled in the art andexamples of such methods include recrystallisation and chromatographictechniques such as column chromatography (e.g. flash chromatography) andHPLC.

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.formulation).

Accordingly, in another embodiment (Embodiment 4.1) of the invention,there is provided a pharmaceutical composition comprising at least onecompound of the formula (1) as defined in any one of Embodiments 1.1 to1.90 together with at least one pharmaceutically acceptable excipient.

In one embodiment (Embodiment 4.2), the composition is a tabletcomposition.

In another embodiment (Embodiment 4.3), the composition is a capsulecomposition.

The pharmaceutically acceptable excipient(s) can be selected from, forexample, carriers (e.g. a solid, liquid or semi-solid carrier),adjuvants, diluents (e.g solid diluents such as fillers or bulkingagents; and liquid diluents such as solvents and co-solvents),granulating agents, binders, flow aids, coating agents,release-controlling agents (e.g. release retarding or delaying polymersor waxes), binding agents, disintegrants, buffering agents, lubricants,preservatives, anti-fungal and antibacterial agents, antioxidants,buffering agents, tonicity-adjusting agents, thickening agents,flavouring agents, sweeteners, pigments, plasticizers, taste maskingagents, stabilisers or any other excipients conventionally used inpharmaceutical compositions.

The term “pharmaceutically acceptable” as used herein means compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof a subject (e.g. a human subject) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each excipient mustalso be “acceptable” in the sense of being compatible with the otheringredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (1) canbe formulated in accordance with known techniques, see for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., USA.

The pharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic,otic, rectal, intra-vaginal, or transdermal administration.

Pharmaceutical dosage forms suitable for oral administration includetablets (coated or uncoated), capsules (hard or soft shell), caplets,pills, lozenges, syrups, solutions, powders, granules, elixirs andsuspensions, sublingual tablets, wafers or patches such as buccalpatches.

Tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as microcrystallinecellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, and starches such as corn starch. Tablets may also containsuch standard ingredients as binding and granulating agents such aspolyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymerssuch as crosslinked carboxymethylcellulose), lubricating agents (e.g.stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT),buffering agents (for example phosphate or citrate buffers), andeffervescent agents such as citrate/bicarbonate mixtures. Suchexcipients are well known and do not need to be discussed in detailhere.

Tablets may be designed to release the drug either upon contact withstomach fluids (immediate release tablets) or to release in a controlledmanner (controlled release tablets) over a prolonged period of time orwith a specific region of the GI tract.

The pharmaceutical compositions typically comprise from approximately 1%(w/w) to approximately 95%, preferably% (w/w) active ingredient and from99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient (forexample as defined above) or combination of such excipients. Preferably,the compositions comprise from approximately 20% (w/w) to approximately90% (w/w) active ingredient and from 80% (w/w) to 10% of apharmaceutically excipient or combination of excipients. Thepharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, pre-filled syringes, dragées, powders,tablets or capsules.

Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5%lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/ or bulking agents(depending on drug dose). They may also contain 0-10% (w/w) polymerbinders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow releasetablets would in addition typically contain 0-99% (w/w)release-controlling (e.g. delaying) polymers (depending on dose). Thefilm coats of the tablet or capsule typically contain 0-10% (w/w)polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50%(w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI)(depending on dose and if freeze dried). Formulations for intramusculardepots may also contain 0-99% (w/w) oils.

The pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a singlepackage, usually a blister pack.

The compounds of the formula (1) will generally be presented in unitdosage form and, as such, will typically contain sufficient compound toprovide a desired level of biological activity. For example, aformulation may contain from 1 nanogram to 2 grams of active ingredient,e.g. from 1 nanogram to 2 milligrams of active ingredient.

Within these ranges, particular sub-ranges of compound are 0.1milligrams to 2 grams of active ingredient (more usually from 10milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1microgram to 20 milligrams (for example 1 microgram to 10 milligrams,e.g. 0.1 milligrams to 2 milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligramto 2 grams, more typically 10 milligrams to 1 gram, for example 50milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect (effective amount). The preciseamounts of compound administered may be determined by a supervisingphysician in accordance with standard procedures.

EXAMPLES

The invention will now be illustrated, but not limited, by reference tothe specific embodiments described in the following examples.

Examples 1-1 to 4-1

The compounds of Examples 1-1 to 4-1 shown in Table 1 below have beenprepared. Their NMR and LCMS properties and the methods used to preparethem are set out in Table 3. The starting materials for each of theExamples are listed in Table 2.

TABLE 1

General Procedures

Where no preparative routes are included, the relevant intermediate iscommercially available. Commercial reagents were utilized withoutfurther purification. Room temperature (rt) refers to approximately20-27° C. ¹H NMR spectra were recorded at 400 MHz on either a Bruker,Varian or Jeol instrument. Chemical shift values are expressed in partsper million (ppm), i.e. (8)-values. The following abbreviations are usedfor the multiplicity of the NMR signals: s=singlet, br=broad, d=doublet,t=triplet, q=quartet, quint=quintet, td=triplet of doublets, tt=tripletof triplets, qd=quartet of doublets, ddd=doublet of doublet of doublets,ddt=doublet of doublet of triplets, m=multiplet. Coupling constants arelisted as J values, measured in Hz. NMR and mass spectroscopy resultswere corrected to account for background peaks. Chromatography refers tocolumn chromatography performed using 60-120 mesh silica gel andexecuted under nitrogen pressure (flash chromatography) conditions. TLCfor monitoring reactions refers to TLC run using the specified mobilephase and Silica gel F254 (Merck) as a stationary phase.Microwave-mediated reactions were performed in Biotage Initiator or CEMDiscover microwave reactors. LCMS experiments were typically carried outusing electrospray conditions as specified for each compound under thefollowing conditions:

LCMS Methods A and B

Instruments: Waters Alliance 2795, Waters 2996 PDA detector, MicromassZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or PhenomenexGemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent D in C(%)]: Method A: 0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2 orMethod B: 0.00/2, 0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2; Solvents:solvent C=2.5 L H₂O+2.5 mL ammonia solution; solvent D=2.5 L MeCN+135 mLH₂O+2.5 mL ammonia solution); Injection volume 3 μL; UV detection 230 to400 nM; column temperature 45° C.; Flow rate 1.5 mL/min.

LCMS Method C

Instruments: Waters Acquity H Class, Photo Diode Array, SQ Detector;Column: BEH C18, 1.7 micron, 2.1×50 mm; Gradient [time (min)/solvent Bin A (%)]: 0.00/5, 0.40/5, 0.8/35, 1.20/55, 2.50/100, 3.30/100 4.00/5;Solvents: solvent A=5 mM Ammonium acetate and 0.1% formic acid in H₂O;solvent B=0.1% formic acid in MeCN; Injection volume 2 μL; UV detection200 to 400 nM; Mass detection 100 to 1200 AMU (+ve electrospray); columnat ambient temperature; Flow rate 0.5 mL/min.

LCMS Method D

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column:X-Bridge C18, 5 micron, 150×4.6mm; Gradient [time (min)/solvent B in A(%)]: 0.00/10, 5.00/90, 7.00/100, 11.00/100, 11.01/10 12.00/10;Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN;Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to1000 AMU (+ve electrospray); column at ambient temperature; Flow rate1.0 mL/min.

LCMS Method E

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column:X-Bridge C18, 5 micron, 150×4.6mm; Gradient [time (min)/solvent B in A(%)]: 0.00/100, 7.00/50, 9.00/0, 11.00/0, 11.01/100, 12.00/100;Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN;Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to1000 AMU (+ve electrospray); column at ambient temperature; Flow rate1.0 mL/min.

LCMS Method F

Instruments: Waters Acquity H Class, Photo Diode Array, SQ Detector;Column: BEH C18, 1.7 micron, 2.1×50 mm; Gradient [time (min)/solvent Bin A (%)]: 0.00/5, 0.40/5, 0.8/35, 1.20/55, 2.70/95, 3.30/5, 4.00/5;Solvents: solvent A =5 mM Ammonium acetate and 0.1% formic acid in H₂O;solvent B=0.1% formic acid in MeCN; Injection volume 2 μL; UV detection200 to 400 nM; Mass detection 100 to 1200 AMU (+ve electrospray); columnat ambient temperature; Flow rate 0.5 mL/min.

LCMS Method G

Instruments: HP 1100 with G1315A DAD, Micromass ZQ; Column: WatersX-Bridge C-18, 2.5 micron, 2.1×20 mm or Phenomenex Gemini-NX C-18, 3micron, 2.0×30 mm; Gradient [time (min)/solvent D in C (%)]: 10.00/2,0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2; Solvents: solvent C=2.5 LH₂O+2.5 mL 28% ammonia in H₂O solution; solvent D=2.5 L MeCN+135 mLH₂O+2.5 mL 28% ammonia in H₂O solution); Injection volume 1 μL; UVdetection 230 to 400 nM; Mass detection 130 to 800 AMU (+ve and —veelectrospray); column temperature 45° C.; Flow rate 1.5 mL/min.

LCMS data in the experimental section are given in the format: Mass ion,retention time, UV activity.

Abbreviations d = day(s) DCE = dichloroethane DCM = dichloromethane DEA= diethylamine DIPEA = diisopropylethylamine DMF = dimethylformamideDMSO = dimethylsulfoxide DPPA = diphenylphosphoryl azide ES = electrospray ionisation Et₃N = triethylamine EtOAc = ethyl acetate h = hour(s)HPLC = high performance liquid chromatography LC = liquid chromatographyLiHMDS = Lithium bis(trimethylsilyl)amide MeCN = acetonitrile MeOH =methanol min = minute(s) MS = mass spectrometry N₂ = nitrogen NMR =nuclear magnetic resonance rt = room temperature sat. = saturated sol. =solution STAB = sodium triacetoxyborohydride TBAF = tetra butyl ammoniumfluoride THF = tetra hydrofuran TLC = thin layer chromatography Prefixesn-, s-, i-, t- and tert- have their usual meanings: normal, secondary,iso, and tertiary.

Synthesis of Intermediates Route 1 Typical Procedure for the Preparationof Ketones as Exemplified by the Preparation of Intermediate 1, ethyl4-(4-acetylpiperidin-1-yl)azepane-1-carboxylate

Azepan-4-one.HCl (5.0 g, 44 mmol) and triethylamine (19.0 mL, 133 mmol)were dissolved in DCM (60 mL) and the solution cooled to 0° C. followedby dropwise addition of ethyl chloroformate (6.3 mL, 66 mmol). Theresulting reaction mixture was stirred at 25° C. for 3 h and thenpartitioned between H₂O (200 mL) and EtOAc (70 mL). The aqueous layerwas further extracted with EtOAc (2×70 mL), combined organics dried overNa₂SO₄ and solvents removed in vacuo. The crude compound was purified bycolumn chromatography (normal silica, mesh size: 60-120, 0 to 0.5% MeOHin DCM) to give ethyl 4-oxoazepane-1-carboxylate (7.8 g, 95%) as a browngum.

LCMS (Method C): m/z 186 (M+H)⁺(ES⁺) at 0.87 min, UV active

Ethyl 4-oxoazepane-1-carboxylate (5.0 g, 27 mmol),piperidine-4-carbonitrile (3.0 g, 27 mmol), ZnCl₂ (1.1 g, 8 mmol) andtriethylamine (19.0 mL, 136 mmol) were dissolved in MeOH (60 mL) and thereaction mixture was stirred at 50° C. for 1 h. The mixture was thencooled to 0° C. before addition of NaBH₃CN (6.8 g, 108 mmol) and furtherstirring at 50° C. for 7 h. The solvents were removed in vacuo and theresidue was partitioned between H₂O (200 mL) and EtOAc (80 mL). Theaqueous layer was extracted with EtOAc (2×80 mL) and combined organicsdried (Na₂SO₄) and concentrated in vacuo. The crude was purified bycolumn chromatography (normal silica, mesh size: 60-120, 0 to 2.0% MeOHin DCM) to give ethyl 4-(4-cyanopiperidin-1-yl)azepane-1-carboxylate(4.0 g, 53%) as a colourless gum.

LCMS (Method D): m/z 280 (M+H)⁺(ES⁺) at 5.13 min, UV active

Ethyl 4-(4-cyanopiperidin-1-yl)azepane-1-carboxylate (300 mg, 0.11 mmol)was dissolved in THF (5 mL) and cooled to 0° C. Methyl magnesium bromide(3 M in ether) (1.5 mL, 4.46 mmol) was added dropwise and the resultingreaction mixture stirred at rt for 4 h. The reaction mixture was dilutedwith water (50 mL) and extracted with EtOAc (30 mL). The aqueous layerwas further extracted with EtOAc (2×30 mL) and combined organics dried(Na₂SO₄) and concentrated in vacuo. The crude compound was purified bycolumn chromatography (normal silica, mesh size: 60-120, 2.0 to 5.0%MeOH in DCM) to give ethyl4-(4-acetylpiperidin-1-yl)azepane-1-carboxylate (210 mg, 66%) as acolourless gum.

The data for the title compound are in Table 2

Route 2 Typical Procedure for the Preparation of Grignard Reagents, asExemplified by the Preparation of Isopentylmagnesium Bromide

To activated magnesium turnings (1.2 g, 49.7 mmol) and iodine (cat.) wasadded anhydrous THF (5 mL). To the mixture was added1-bromo-3-methylbutane (5.0 g, 33.1 mmol) dropwise and the reactioninitiated with a heat gun. The resulting reaction mixture was dilutedwith anhydrous THF (35 mL) and the reaction further stirred for 2 h at60° C. The crude mixture was used directly for the next step.

Route 3 Typical Procedure for the Preparation of Ketones, as Exemplifiedby the Preparation of Intermediate 11, ethyl(4S)-4-(4-acetylpiperidin-1-yl)azepane-1-carboxylate

Ethyl (4R)-4-hydroxyazepane-1-carboxylate (2.0 g, 10.7 mmol) andtriethylamine (3.0 mL, 21.2 mmol) were dissolved in DCM (20 mL) at 0°C., and to the solution was added methanesulfonyl chloride (1.2 mL, 16.0mmol) dropwise and the resulting reaction mixture stirred at 25° C. for2 h. The mixture was partitioned between H₂O (150 mL) and EtOAc (80 mL),the aqueous layer further extracted with EtOAc (2×80 mL) and combinedorganics dried (Na₂SO₄) and solvents removed in vacuo. The residue waspurified by column chromatography (normal silica, mesh size: 60-120, 0to 0.5% MeOH in DCM) to give ethyl(4R)-4-[(methylsulfonyl)oxy]azepane-1-carboxylate (2.5 g, 84%) as ayellow liquid.

LCMS (Method D): m/z 266 (M+H)⁺(ES⁺) at 5.18 min, UV active

Piperidine-4-carbonitrile (1.0 g, 9.1 mmol) was dissolved in THF (20 mL)before addition of K₂OC₃ (3.8 g, 27.3 mmol). The resulting reactionmixture was cooled to 0 ° C. and ethyl(4R)-4-[(methylsulfonyl)oxy]azepane-1-carboxylate (2.0 g, 7.5 mmol)added dropwise. The resulting reaction mixture was stirred at 80° C. for50 h. The solvents were removed in vacuo, the residue partitionedbetween H₂O (200 mL) and EtOAc (110 mL) and the aqueous layer furtherextracted with EtOAc (2×110 mL). Combined organics were dried (Na₂SO₄)and the residue purified by column chromatography (normal silica, meshsize: 60-120, 4 to 8% MeOH in DCM) to give ethyl(4S)-4-(4-cyanopiperidin-1-yl)azepane-1-carboxylate (1.6 g, 76%) as ayellow gum.

LCMS (Method C): m/z 280 (M+H)⁺(ES⁺) at 1.49 min, UV active

Ethyl (4S)-4-(4-cyanopiperidin-1-yl)azepane-1-carboxylate (400 mg, 1.4mmol) was dissolved in THF (10 mL) and reaction mixture stirred at 0° C.for 30 min. Methyl magnesium bromide (3 M sol in ether) (2.0 mL, 5.9mmol) was added dropwise and the resulting reaction mixture was stirredat 25° C. for 4 h. The solvents were removed in vacuo and the residuepartitioned between H₂O (60 mL) and EtOAc (40 mL). The aqueous layer wasfurther extracted with EtOAc (2×40 mL), and combined organics dried(Na₂SO₄) and the residue purified by column chromatography (normalsilica, mesh size: 60-120, 2 to 5% MeOH in DCM) to give ethyl(4S)-4-(4-acetylpiperidin-1-yl)azepane-1-carboxylate, intermediate 11(300 mg, 71%) as a colourless gum. The data for the title compound arein Table 2.

Route 4 Typical Procedure for the Preparation of Ketones, as Exemplifiedby the Preparation of Intermediate 16, ethyl2-(4-acetylpiperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate

Tert-butyl-2-oxo-6-azaspiro[3.4]octane-6-carboxylate (1.0 g, 4.4 mmol)was dissolved in DCM (10 mL) and trifluoroacetic acid (0.7 mL, 8.9 mmol)was added dropwise. The resulting mixture was stirred at 30° C. for 16 hand the solvents removed in vacuo. The residue was purified bytrituration with ether (3×5 mL) to give 6-azaspiro[3.4]octan-2-one. TFA(600 mg, 56%) as an off white solid.

LCMS (Method D): m/z 126 (M+H)⁺(ES⁺) at 3.37 min, UV active

To 6-azaspiro[3.4]octan-2-one.TFA (1.0 g, 8.0 mmol) and triethylamine(2.8 mL, 20.0 mmol) in DCM (10 mL) at 0° C. was added ethylchloroformate (1.1 mL, 12.0 mmol) dropwise and the resulting reactionmixture stirred at 25° C. for 3 h. The mixture was then partitionedbetween H₂O (80 mL) and EtOAc (50 mL), the aqueous layer furtherextracted with EtOAc (2×50 mL) and combined organics dried (Na₂SO₄). Thesolvents were removed in vacuo and the crude residue purified by columnchromatography (normal silica, mesh size: 60-120, 0 to 0.5% MeOH in DCM)to give ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (1.40 g, 89%) asan off white solid.

LCMS (Method C): m/z 198 (M+H)⁺(ES⁺) at 1.75 min, UV active

Ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (1.00 g, 5.1 mmol),piperidine-4-carbonitrile (0.61 g, 5.6 mmol), ZnCl₂ (0.21 g, 0.2 mmol)and triethylamine (3.6 mL, 25.3 mmol) were dissolved in MeOH (15 mL) andthe reaction mixture stirred at 50° C. for 1 h. The mixture was thencooled to 0° C. and NaBH₃CN (1.30 g, 20.3 mmol) added portionwise beforefurther stirring at 50° C. for 7 h. The solvents were then removed invacuo, and the resulting residue partitioned between H₂O (100 mL) andEtOAc (60 mL). The aqueous layer was extracted with EtOAc (2×60 mL), andcombined organics dried over Na₂SO₄. The residue was purified by columnchromatography (normal silica, mesh size: 60-120, 0.5 to 4.0% MeOH inDCM) to give ethyl2-(4-cyanopiperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate (1.40 g,81%) as a yellow gum.

LCMS (Method C): m/z 293 (M+H)⁺(ES⁺) at 1.53 min, UV active

Ethyl 2-(4-cyanopiperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate (200mg, 0.69 mmol) was dissolved in THF (5 mL) and the reaction mixturestirred at 0° C. for 30 min. Methyl magnesium bromide (1.4 M sol inether) (2.0 mL, 2.85 mmol) was then added dropwise and the resultingreaction mixture stirred at 25° C. for 4 h. The solvent was removed invacuo and the residue partitioned between H₂O (40 mL) and EtOAc (25 mL).The aqueous layer was extracted with EtOAc (2×25 mL) and combinedorganics were dried over Na₂SO₄. The residue was purified by columnchromatography (normal silica, mesh size: 60-120, 1.0 to 3.0% MeOH inDCM) to give ethyl2-(4-acetylpiperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate (150 mg,71%) as a yellow gum.

The data for the title compound are in Table 2.

Route 5 Procedure for the Preparation of Carboxylic Acid Intermediate21, 1-[1-(ethoxycarbonyl)azepan-4-yl]piperidine-4-carboxylic Acid

Azepan-4-one.HCl (5.0 g, 44 mmol) and triethylamine (19.0 mL, 133 mmol)were dissolved in DCM (60 mL) at 0° C. followed by dropwise addition ofethyl chloroformate (6.3 mL, 66 mmol). The resulting reaction mixturewas stirred at 25° C. for 3 h and the mixture partitioned between H₂O(200 mL) and EtOAc (70 mL). The aqueous layer was further extracted withEtOAc (2×70 mL) and combined organics dried (Na₂SO₄) and solventsremoved in vacuo. The crude compound was purified by columnchromatography (normal silica, mesh size: 60-120, 0 to 0.5% MeOH in DCM)to give ethyl 4-oxoazepane-1-carboxylate (7.8 g, 95%) as a brown gum.

LCMS (Method C): m/z 186 (M+H)⁺(ES⁺) at 0.87 min, UV active

Ethyl 4-oxoazepane-1-carboxylate (3.0 g, 16.2 mmol), ethylpiperidine-4-carboxylate (2.5 g, 16.2 mmol) and triethylamine (8.1 g,81.0 mmol) were dissolved in MeOH (50 mL) and the reaction mixturedegassed with nitrogen for 30 min. ZnCl₂ (110 mg, 0.8 mmol) was addedand the mixture stirred at 60° C. for 3 h. The reaction mixture wascooled to 0° C., NaCNBH₃ (5.1 g, 81.0 mmol) was added portionwise andthe mixture stirred at rt for 8 h. The mixture was diluted with water(500 mL), extracted with DCM (3×150 mL) and combined organics dried overNa₂SO₄ and concentrated in vacuo. The crude product was purified bycolumn chromatography (normal phase, neutral silica gel, 60-120 mesh, 0to 1% MeOH in DCM) to give ethyl4-(4-(ethoxycarbonyl)piperidin-1-yl)azepane-1-carboxylate (2.5 g, 47%)as a yellow gum.

LCMS (Method F): m/z 328 (M+H)⁺(ES⁺) at 2.52 min, UV active

Ethyl 4-(4-(ethoxycarbonyl)piperidin-1-yl)-azepane-1-carboxylate (2.3 g,7.0 mmol), LiOH (0.34 g, 14.1 mmol) and H₂O (15mL) were dissolved in THF(15 mL) and the resulting reaction mixture stirred at 80° C. for 16 h.The solvents were removed in vacuo and the residue partitioned betweenH₂O (80 mL) and EtOAc (50 mL). The aqueous layer was extracted withEtOAc (2×50 mL) and combined organics dried over Na₂SO₄. The cruderesidue was purified by column chromatography (normal silica, mesh size:60-120, 6 to 10% MeOH in DCM) to give1-(1-(ethoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic acid,intermediate 21 (1.4 g, 70%) as a white solid.

The data for the title compound are in Table 2.

General Synthetic Procedures Route a Typical Procedure for thePreparation of Oximes, as Exemplified by the Preparation of Example 1-1,Ethyl 4-{4-[N-methoxyethanimidoyl]piperidin-1-yl}azepane-1-carboxylate

To a solution of ethyl 4-(4-acetylpiperidin-1-yl)azepane-1-carboxylate(200 mg, 0.68 mmol) in MeOH (5 mL) was added 0-methyl hydroxylaminehydrochloride (85 mg, 1.01 mmol) and sodium acetate (83 mg, 1.01 mmol)at rt and the resulting reaction mixture stirred for 8 h. The solventwas removed in vacuo, the residue partitioned between H₂O (50 mL) andEtOAc (30 mL) and the aqueous layer further extracted with EtOAc (2×30mL). Combined organics were dried (Na₂SO₄) and the solvent removed invacuo. The crude compound was purified by Prep HPLC [reverse phase HPLC(X-Bridge, C-18, 250×19 mm, 5 μm, 19 mL per min, gradient 40 to 45%(over 15 min),100% (over 2.0 min) then 40% (over 4.0 min), 0.1% NH₃ inMeCN/water] to give ethyl4-{4-[N-methoxyethanimidoyl]piperidin-1-yl}azepane-1-carboxylateIsomer-1, (5 mg, 2.3%) as a colourless gum and Isomer-2, (25 mg, 11.0%)as a colourless gum. The data for the title compound are in Table 3.

Route b Procedure for the Preparation of Example 3-1, ethyl4-{4-[N′-methoxy-N-(2-methylpropyl)carbamimidoyl]piperidin-1-yl}azepane-1-carboxylate

1-(1-(Ethoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic acid (1.0 g,33.5 mmol) and HATU (1.4 g, 36.8 mmol) were dissolved in MeCN (20 mL)and the reaction stirred at rt for 15 min. 0-methyl hydroxylaminehydrochloride (308 mg, 36.8 mmol) and DIPEA (1.27 g, 99.5 mmol) wereadded and the mixture further stirred at rt for 4 h. The mixture wasquenched with water (150 mL), extracted with DCM (3×60 mL) and combinedorganics dried over Na₂SO₄ and concentrated in vacuo. The crude residuewas purified by column chromatography (normal phase, neutral silica gel,60-120 mesh, 0 to 8% MeOH in DCM) to give ethyl4-[4-(methoxycarbamoyl)piperidin-1-yl]azepane-1-carboxylate (400 mg,36%) as a yellow gum.

Ethyl 4[4-(methoxycarbamoyl)piperidin-1-yl]azepane-1-carboxylate (250mg, 0.76 mmol) was dissolved in MeOH and thionyl chloride (135 mg, 1.14mmol) added at 0 ° C. The mixture was then stirred at rt for 3 h, cooledto 0° C. and basified with a saturated solution of NaHCO₃. The mixturewas diluted with water (60 mL), extracted with DCM (3×20 mL) andcombined organics dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was purified by column chromatography (normal phase, neutralsilica gel, 60-120 mesh, 0 to 2.5% MeOH in DCM) to give ethyl4-{4-[chloro(methoxyimino)methyl]piperidin-1-yl}lazepane-1-carboxylate(100 mg, 38%) as a yellow gum.

LCMS (Method C): m/z 346 (M+H)⁺(ES⁺) at 1.70 min, UV active

Ethyl4-{4-[(E)-chloro(methoxyimino)methyl]piperidin-1-yl}azepane-1-carboxylate,K₂OC₃ and 2-methylpropan-1-amine were dissolved in DMF and the mixtureallowed to stir at 90° C. for 3 h. The reaction mixture was then dilutedwith water (60 mL), extracted with DCM (3×20 mL) and combined organicsdried over Na₂SO₄ and concentrated in vacuo. The crude product waspurified by column chromatography (normal phase, neutral silica gel,60-120 mesh, 0 to 4% MeOH in DCM) to give ethyl4-{4-[N′-methoxy-N-(2-methylpropyl)carbamimidoyl]piperidin-1-yl}azepane-1-carboxylate,example 3-1 (25 mg, 32%) as a brown gum.

The data for the title compound are in Table 3.

Route c Procedure for the Preparation of Example 4-1, ethyl4-(4-{cyano[(propan-2-yloxy)imino]methyl}piperidin-1-yl)azepane-1-carboxylate

To a solution of1-(1-(ethoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic acid (0.72 g,2.41 mmol) in DMF (10 mL) was added HATU (1.37 g, 3.61 mmol),O-isopropylhydroxylamine.HCl (0.30 g, 2.65 mmol) and DIPEA (1.26 mL,7.23 mmol) and the resulting mixture stirred at rt for 65 h. The solventwas removed in vacuo and the residue diluted with DCM and washed withNaHCO₃ and brine. Organics were dried over MgSO₄ and concentrated invacuo. The residue was purified on silica (25 g SNAP cartridge, 0-9%MeOH in DCM) to yield the desired product ethyl4-{4-[(propan-2-yloxy)carbamoyl]piperidin-1-yl}azepane-1-carboxylate(101 mg, 12%) as a yellow gum.

LCMS (Method B): m/z 356 (M+H)⁺(ES⁺) at 2.58 min, UV inactive.

To a solution of ethyl4-{4-[(propan-2-yloxy)carbamoyl]piperidin-1-yl}azepane-1-carboxylate (96mg, 0.27 mmol) in anhydrous 1,2-dichloroethane (10 mL) was addedphosphorus oxychloride (45 mg, 0.29 mmol) and the mixture heated to 85°C. for 16 h. The mixture was then allowed to cool to rt before quenchingwith ice. The mixture was then diluted with sat. aq. NaHCO₃ andextracted with DCM (2×20 mL). Combined organics were dried over MgSO₄,filtered and concentrated in vacuo to yield ethyl4-(4-{chloro[(propan-2-yloxy)imino]methyl}piperidin-1-yl)azepane-1-carboxylate(99 mg, 100%) as an amber gum, which was taken on directly to the nextstep.

To a stirred solution of ethyl4-(4-{chloro[(propan-2-yloxy)imino]methyl}piperidin-1-yl)azepane-1-carboxylate(99 mg, 0.27 mmol) in anhydrous DMSO (2 mL) was added sodium cyanide (26mg, 0.54 mmol) and the solution heated to 95° C. under N₂ for 7 h beforeaddition of further sodium cyanide (26 mg, 0.54 mmol) and heating at 95°C. for 48 h. A further portion of sodium cyanide (26 mg, 0.54 mmol) wasthen added and the mixture heated to 110° C. for 16 h. The mixture wasthen allowed to cool to rt and concentrated in vacuo. The residue wasdiluted with DCM and washed with 5% potassium carbonate (aq.) (20 mL×1)and brine (20 mL×1). The organic layer was dried over MgSO₄, filteredand concentrated in vacuo. The residue was purified on silica (0-5% MeOHin DCM) to yield ethyl4-(4-{cyano[(propan-2-yloxy)imino]methyl}piperidin-1-yl)azepane-1-carboxylate,example 4-1 (5.0 mg, 5%) as a colourless oil.

The data for the title compound are in Table 3.

TABLE 2 Starting Materials and Intermediates Intermediate Route NameData  1 Route 1 and Ethyl 4-(4-acetylpiperidin-1- LCMS (Method C): m/zintermediate yl)azepane-1-carboxylate 297 (M + H)+ (ES+), at 1.48 2 min,UV active  2 4-Azepanone. HCl Commercially available, CAS: 50492-22-3  3Route 1 and Ethyl 4-(4-propanoylpiperidin- LCMS (Method F): m/zintermediates 1-yl)azepane-1-carboxylate 311 (M + H)+ (ES+), at 0.48 2and 7 min, UV active  4 Route 1 and Ethyl 4-(4-butanoylpiperidin-1- LCMS(Method D): m/z intermediates yl)azepane-1-carboxylate 325 (M + H)+(ES+), at 6.27 2 and 8 min, UV active  5 Route 1 and Ethyl 4-[4-(2- LCMS(Method F): m/z intermediates methylpropanoyl)piperidin-1- 325 (M + H)+(ES+), at 1.66 2 and 9 yl]azepane-1-carboxylate min, UV active  6 Route1 and 2 Ethyl 4-[4-(4- LCMS (Method D): m/z andmethylpentanoyl)piperidin-1- 353 (M + H)+ (ES+), at 7.21 intermediatesyl]azepane-1-carboxylate min, UV active 2 and 10  7 Ethyl magnesiumbromide Commercially available, CAS: 925-90-6  8 Propyl magnesiumbromide Commercially available, CAS: 927-77-5  9 Isopropyl magnesiumbromide Commercially available, CAS: 920-39-8 10 1-Bromo-3-methylbutaneCommercially available, CAS: 107-82-4 11 Route 3 and Ethyl(4S)-4-(4-acetylpiperidin- LCMS (Method C): m/z intermediate1-yl)azepane-1-carboxylate 297 (M + H)+ (ES+), at 1.51 12 min, UV active12 Ethyl (4R)-4-hydroxyazepane- 1H NMR (400 MHz, CDCl3) 1-carboxylate δ:1.26 (t, 3 H), 1.50 (bs, 1 H), 1.62-2.05 (m, 6H), 3.28-3.52 (m, 4 H),3.89 (m, 1 H), 4.13 (m, 2 H) 13 Route 3 and Ethyl (4S)-4-(4- LCMS(Method D): m/z intermediates propanoylpiperidin-1- 311 (M + H)+ (ES+),at 5.81 7 and 12 yl)azepane-1-carboxylate min, UV active 14 Route 3 andEthyl (4S)-4-(4- LCMS (Method C): m/z intermediates butanoylpiperidin-1-325 (M + H)+ (ES+), at 1.69 8 and 12 yl)azepane-1-carboxylate min, UVactive 15 Route 3 and Ethyl (4S)-4-[4-(2- LCMS (Method C): m/zintermediates methylpropanoyl)piperidin-1- 325 (M + H)+ (ES+), at 1.59 9and 12 yl]azepane-1-carboxylate min, UV active 16 Route 4 and Ethyl2-(4-acetylpiperidin-1-yl)- LCMS (Method C): m/z intermediate6-azaspiro[3.4]octane-6- 310 (M + H)+ (ES+), at 1.59 17 carboxylate min,UV active 17 Tert-butyl 2-oxo-6- Commercially available,azaspiro[3.4]octane-6- CAS: 203661-71-6 carboxylate 18 Route 4 and Ethyl2-(4-propanoylpiperidin- LCMS (Method C): m/z intermediates1-yl)-6-azaspiro[3.4]octane-6- 323 (M + H)+ (ES+), at 1.62 17 and 7carboxylate min, UV active 19 Route 4 and Ethyl2-(4-butanoylpiperidin-1- m/z 338 (M + H)+ (ES+) intermediatesyl)-6-azaspiro[3.4]octane-6- 17 and 8 carboxylate 20 Ethylpiperidine-4-carboxylate Commercially available, CAS: 1126-09-6 21 Route5 and 1-[1-(Ethoxycarbonyl)azepan- LCMS (Method C): m/z intermediates4-yl]piperidine-4-carboxylic 299 (M + H)+ (ES+), at 1.45 20 and 2 acidmin, UV active 22 O-Methyl hydroxylamine Commercially available,hydrochloride CAS: 593-56-6 23 O-Ethylhydroxylamine Commerciallyavailable, hydrochloride CAS: 3332-29-4 24 O-PropylhydroxylamineCommercially available, hydrochloride CAS: 6084-54-4 25O-Isopropylhydroxylamine Commercially available, hydrochloride CAS:4490-81-7 29 2-Methylpro pan-1-amine Commercially available, CAS:78-81-9 30 Ethyl chloroformate Commercially available, CAS: 541-41-3 31Piperidine-4-carbonitrile Commercially available, CAS: 4395-98-6 32Methyl magnesium bromide Commercially available, CAS: 75-16-1

TABLE 3 Ex. Inter- Synthetic LCMS No. Name mediates method ¹H NMR MethodLCMS data 1-1 Isomer 1 (racemic): Ethyl 1 a 400 MHz, (MeOD-d₄) δ:1.26-1.31 (m, 7 H), 1.47-1.72 E m/z 326 (M + H)⁺ (ES⁺) 4-{4-[N-methoxy(m, 8 H), 1.81 (s, 3 H), 1.93-2.12 (m, 4 H), 2.90-3.17 at 5.93 min, UVactive ethanimidoyl]piperidin-1- (m, 2 H), 3.56-3.67 (m, 2 H), 3.78 (s,3 H), 4.11-4.17 yl}azepane-1-carboxylate (m, 2 H) 1.1 Isomer 2(racemic): Ethyl 1 a 400 MHz, (DMSO-d₆) δ: 1.17 (td, J = 7.0, 2.0 Hz, 3H), E m/z 326 (M + H)⁺ (ES⁺) 4-{4-[N-methoxy 1.33-1.84 (m, 13 H),1.99-2.23 (m, 3 H), 2.32-2.44 at 6.22 min, UV activeethanimidoyl]piperidin-1- (m, 1 H), 2.66-2.80 (m, 2 H), 3.16-3.27 (m, 2H), 3.39- yl}azepane-1-carboxylate 3.49 (m, 2 H), 3.71 (s, 3 H), 4.03(qd, J = 7.0, 2.5 Hz, 2 H) (S)- Isomer 1: Ethyl (4S)-4-{4- 11 a 400 MHz,(DMSO-d₆) δ: 1.17 (td, J = 7.0, 2.0 Hz, 3 D m/z 326 (M + H)⁺ (ES⁺) 1-1[N-methoxy H), 1.28-1.63 (m, 7 H), 1.71 (s, 3 H), 1.74-1.89 (m, 3 at5.99 min, UV active ethanimidoyl]piperidin-1- H), 2.03-2.47 (m, 2 H),2.60-2.98 (m, 4 H), 3.17-3.24 yl}azepane-1-carboxylate (m, 2 H),3.41-3.52 (m, 2 H), 3.70 (s, 3 H), 4.03 (qd, J = 7.0, 3.0 Hz, 2 H) (S)-Isomer 2: Ethyl (4S)-4-{4- 11 a 400 MHz, (DMSO-d₆) δ: 1.17 (td, J = 7.0,2.0 Hz, 3 H), D m/z 326 (M + H)⁺ (ES⁺) 1-1 [N-methoxy 1.34-1.63 (m, 7H), 1.72 (s, 3 H), 1.73-1.86 (m, 3 H), at 6.29 min, UV activeethanimidoyl]piperidin-1- 1.99-2.20 (m, 3 H), 2.32-2.45 (m, 1 H),2.66-2.81 (m, yl}azepane-1-carboxylate 2 H), 3.16-3.25 (m, 2 H),3.41-3.49 (m, 2 H), 3.71 (s, 3 H), 4.03 (qd, J = 7.0, 2.5 Hz, 2 H) 1-2Isomer 1 (racemic): Ethyl 3 a 400 MHz, (DMSO-d₆) δ: 0.99 (t, J = 7.5 Hz,3 H), 1.16- E m/z 340 (M + H)⁺ (ES⁺) 4-{4-[N-methoxy 1.18 (m, 3 H),1.28-1.62 (m, 7 H), 1.70-1.85 (m, 3 H), at 6.77 min, UV activepropanimidoyl]piperidin-1- 2.09-2.23 (m, 4 H), 2.32-2.43 (m, 1 H),2.65-2.90 (m, yl}azepane-1-carboxylate 3 H), 3.14-3.28 (m, 2 H),3.39-3.50 (m, 2 H), 3.71 (s, 3 H), 4.00-4.05 (m, 2 H) 1-2 Isomer 2(racemic): Ethyl 3 a 400 MHz, (DMSO-d₆) δ: 0.98 (t, J = 7.5 Hz, 3 H),1.17 G m/z 340 (M + H)⁺ (ES⁺) 4-{4-[N-methoxy (td, J = 7.0, 2.0 Hz, 3H), 1.34-1.86 (m, 10 H), 2.03-2.21 at 4.44 min, UV activepropanimidoyl]piperidin-1- (m, 5 H), 2.39-2.43 (m, 1 H), 2.69-2.82 (m, 2H), 3.16- yl}azepane-1-carboxylate 3.25 (m, 2 H), 3.39-3.52 (m, 2 H),3.70 (s, 3 H), 4.03 (qd, J = 7.0, 2.5 Hz, 2 H) (S)- Isomer 1: Ethyl(4S)-4-{4- 13 a 400 MHz, (DMSO-d₆) δ: 0.99 (t, J = 7.0 Hz, 3 H), 1.17 Cm/z 340 (M + H)⁺ (ES⁺) 1-2 [N-methoxy (t, J = 6.0 Hz, 3 H), 1.25-1.65(m, 7 H), 1.67-1.87 (m, 3 at 1.69 min, UV activepropanimidoyl]piperidin-1- H), 2.11-2.27 (m, 4 H), 2.31-2.43 (m, 1 H),2.65-2.91 yl}azepane-1-carboxylate (m, 3 H), 3.13-3.27 (m, 2 H),3.39-3.51 (m, 2 H), 3.72 (s, 3 H), 3.98-4.09 (m, 2 H) (S)- Isomer 2:Ethyl (4S)-4-{4- 13 a 400 MHz, (DMSO-d₆) δ: 0.98 (t, J = 7.5 Hz, 3 H),1.17 C m/z 340 (M + H)⁺ (ES⁺) 1-2 [N-methoxy (td, J = 7.0, 2.0 Hz, 3 H),1.29-1.89 (m, 10 H), 2.01-2.21 at 1.74 min, UV activepropanimidoyl]piperidin-1- (m, 5 H), 2.34-2.44 (m, 1 H), 2.66-2.80 (m, 2H), 3.16- yl}azepane-1-carboxylate 3.28 (m, 2 H), 3.39-3.49 (m, 2 H),3.71 (s, 3 H), 4.03 (qd, J = 7.0, 2.0 Hz, 2 H) 1-3 Isomer 1 (racemic):Ethyl 4 a 400 MHz, (DMSO-d₆) δ: 0.88 (t, J = 7.5 Hz, 3 H), 1.17 C m/z354 (M + H)⁺ (ES⁺) 4-{4-[N- (td, J = 7.0, 2.0 Hz, 3 H), 1.30-1.63 (m, 9H), 1.70-1.87 at 1.77 min, UV active methoxybutanimidoyl] (m, 3 H), 2.07(t, J = 7.5 Hz, 2 H), 2.11-2.24 (m, 2 H), piperidin-1-yl}azepane-1-2.70-2.89 (m, 3 H), 3.12-3.27 (m, 2 H), 3.40-3.54 (m, 3 carboxylate H),3.71 (s, 3 H), 4.03 (qd, J = 7.0, 2.5 Hz, 2 H) 1-3 Isomer 2 (racemic):Ethyl 4 a 400 MHz, (DMSO-d₆) δ: 0.87 (t, J = 7.5 Hz, 3 H), 1.17 C m/z354 (M + H)⁺ (ES⁺) 4-{4-[N- (td, J = 7.0, 2.0 Hz, 3 H), 1.27-1.88(m, 13H), 1.96-2.28 at 1.82 min, UV active methoxybutanimidoyl] (m, 4 H),2.32-2.45 (m, 1 H), 2.66-2.86 (m, 2 H), 3.16- piperidin-1-yl}azepane-1-3.25 (m, 2 H), 3.41-3.52 (m, 2 H), 3.70 (s, 3 H), 4.03 carboxylate (qd,J = 7.0, 2.5 Hz, 2 H) (S)- Isomer 1: Ethyl (4S)-4-{4- 14 a 400 MHz,(MeOD-d₄) δ: 0.96 (t, J = 7.5 Hz, 3 H), 1.26- D m/z 354 (M + H)⁺ (ES⁺)1-3 [N-methoxy 1.31 (m, 4 H), 1.44-1.77 (m, 8 H), 1.91-2.18 (m, 6 H), at7.45 min, UV active butanimidoyl]piperidin-1- 2.35-2.51 (m, 2 H),2.55-2.65 (m, 1 H), 2.85-3.04 (m, yl}azepane-1-carboxylate 3 H),3.36-3.40 (m, 1 H), 3.54-3.61 (m, 2 H), 3.79 (s, 3 H), 4.11-4.17 (m, 2H) (S)- Isomer 2: Ethyl (4S)-4-{4- 14 a 400 MHz, (MeOD-d₄) δ: 0.95 (t, J= 7.5 Hz, 3 H), 1.26- D m/z 354 (M + H)⁺ (ES⁺) 1-3 [N-methoxy 1.31 (m, 4H), 1.48-1.81 (m, 9 H), 1.91-2.26 (m, 6 H), at 7.61 min, UV activebutanimidoyl]piperidin-1- 2.37-2.46 (m, 2 H), 2.57-2.62 (m, 1 H),2.87-2.97 (m, yl}azepane-1-carboxylate 2 H), 3.36-3.41 (m, 1 H),3.54-3.62 (m, 2 H), 3.77 (s, 3 H), 4.11-4.17 (m, 2 H) 1-4 Isomer 1(racemic): Ethyl 5 a 400 MHz, (MeOD-d₄) δ: 1.12 (d, J = 7.0 Hz, 6 H),1.26- C m/z 354 (M + H)⁺ (ES⁺) 4-{4-[N-methoxy-2- 1.31 (m, 5 H),1.46-1.78 (m, 6 H), 1.87-2.61 (m, 6 H), at 1.79 min, UV activemethylpropanimidoyl] 2.83-2.94 (m, 2 H), 3.05-3.12 (m, 1 H), 3.24 (q, J= 7.0 piperidin-1-yl}azepane-1- Hz, 2 H), 3.54-3.62 (m, 2 H), 3.76 (s, 3H), 4.11-4.17 carboxylate (m, 2 H) 1-4 Isomer 2 (racemic): Ethyl 5 a 400MHz, (DMSO-d₆) δ: 1.03 (d, J = 7.0 Hz, 6 H), 1.11 G m/z 354 (M + H)⁺(ES⁺) 4-{4-[N-methoxy-2- (t, J = 7.0 Hz, 2 H), 1.17 (td, J = 7.0, 2.5Hz, 3 H), 1.32- at 4.84 min, UV active methylpropanimidoyl] 1.85 (m, 7H), 2.06-2.20 (m, 3 H), 2.37-2.41 (m, 1 H), piperidin-1-yl}azepane-1-2.66-2.78 (m, 2 H), 2.93-3.06 (m, 2 H), 3.17-3.25 (m, carboxylate 2 H),3.39-3.44 (m, 2 H), 3.69 (s, 3 H), 4.03 (qd, J = 7.0, 3.0 Hz, 2 H) 1-5Isomer 1 (racemic): Ethyl 15 a 400 MHz, (MeOD-d₄) δ: 1.11 (d, J = 6.5Hz, 6 H), 1.26- C m/z 354 (M + H)⁺ (ES⁺) 4-{4-[N-methoxy-2- 1.31 (m, 4H), 1.43-1.73 (m, 5 H), 1.91-2.06 (m, 5 H), at 1.79 min, UV activemethylpropanimidoyl] 2.35-2.38 (m, 2 H), 2.52-2.59 (m, 2 H), 2.75-2.90(m, piperidin-1-yl}azepane-1- 3 H), 3.24 (q, J = 7.0 Hz, 1 H), 3.55-3.61(m, 2 H), 3.77 carboxylate (s, 3 H), 4.11-4.17 (m, 2 H) 1-5 Isomer 2(racemic): Ethyl 15 a 400 MHz, (MeOD-d₄) δ: 1.12 (d, J = 7.0 Hz, 6 H),1.26- C m/z 354 (M + H)⁺ (ES⁺) 4-{4-[N-methoxy-2- 1.31 (m, 4 H),1.47-1.79 (m, 7 H), 1.91-2.06 (m, 3 H), at 1.86 min, UV activemethylpropanimidoyl] 2.18-2.60 (m, 4 H), 2.85-2.96 (m, 2 H), 3.06-3.13(m, piperidin-1-yl}azepane-1- 1 H), 3.24 (q, J = 7.5 Hz, 1 H), 3.54-3.61(m, 2 H), 3.76 carboxylate (s, 3 H), 4.11-4.17 (m, 2 H) 1-6 Isomer 1(racemic): Ethyl 6 a 400 MHz, (DMSO-d₆) δ: 0.87 (d, J = 6.5 Hz, 6 H),1.15- C m/z 382 (M + H)⁺ (ES⁺) 4-{4-[N-methoxy-4- 1.86 (m, 16 H),2.07-2.23 (m, 4 H), 2.36-2.40 (m, 1 H), at 1.97 min, UV activemethylpentanimidoyl] 2.68-2.89 (m, 3 H), 3.13-3.28 (m, 2 H), 3.40-3.50(m, piperidin-1-yl}azepane-1- 2 H), 3.70 (s, 3 H), 4.03 (qd, J = 7.0,2.0 Hz, 2 H) carboxylate 1-6 Isomer 2 (racemic): Ethyl 6 a 400 MHz,(DMSO-d₆) δ: 0.87 (d, J = 6.5 Hz, 6 H), 1.15- C m/z 382 (M + H)⁺ (ES⁺)4-{4-[N-methoxy-4- 1.85 (m, 16 H), 2.07-2.21 (m, 4 H), 2.36-2.40 (m, 1H), at 2.00 min, UV active methylpentanimidoyl] 2.68-2.88 (m, 3 H),3.14-3.27 (m, 2 H), 3.40-3.49 (m, piperidin-1-yl}azepane-1- 2 H), 3.70(s, 3 H), 3.40-4.05 (m, 2 H) carboxylate 1-7 Isomer 1 (racemic): Ethyl 1and 23 a 400 MHz, (DMSO-d₆) δ: 1.13-1.89 (m, 18 H), 2.11-2.26 E m/z 340(M + H)⁺ (ES⁺) 4-{4-[N-ethoxy (m, 2 H), 2.34-2.44 (m, 1 H), 2.68-2.93(m, 4 H), 3.16- at 6.50 min, UV active ethanimidoyl]piperidin-1- 3.24(m, 2 H), 3.42-3.47 (m, 2 H), 3.95 (q, J = 7.0 Hz, 2yl}azepane-1-carboxylate H), 4.03 (qd, J = 7.0, 3.0 Hz, 2 H) 1-7 Isomer2 (racemic): Ethyl 1 and 23 a 400 MHz, (DMSO-d₆) δ: 1.14-1.19 (m, 6 H),1.31-1.85 E m/z 340 (M + H)⁺ (ES⁺) 4-{4-[N-ethoxy (m, 13 H), 2.01-2.22(m, 3 H), 2.32-2.46 (m, 1 H), 2.68- at 6.60 min, UV activeethanimidoyl]piperidin-1- 2.74 (m, 2 H), 3.16-3.25 (m, 2 H), 3.41-3.46(m, 2 H), yl}azepane-1-carboxylate 3.94-4.06 (m, 4 H) 1-8 Isomer 1(racemic): Ethyl 1 and 24 a 400 MHz, (DMSO-d₆) δ: 0.84-0.89 (m, 3 H),1.15-1.19 E m/z 354 (M + H)⁺ (ES⁺) 4-{4-[N-propoxy (td, J = 7.0, 2.0 Hz,3 H), 1.34-1.87 (m, 15 H), 2.15- at 7.15 min, UV activeethanimidoyl]piperidin-1- 2.23 (m, 2 H), 2.33-2.44 (m, 1 H), 2.68-2.91(m, 3 H), yl}azepane-1-carboxylate 3.16-3.24 (m, 2 H), 3.41-3.51 (m, 2H), 3.87 (q, J = 6.5 Hz, 2 H), 4.03 (qd, J = 7.0, 3.0 Hz, 2 H) 1-8Isomer 2 (racemic): Ethyl 1 and 24 a 400 MHz, (DMSO-d₆) δ: 0.87 (t, J =7.5 Hz, 3 H), 1.17 E m/z 354 (M + H)⁺ (ES⁺) 4-{4-[N-propoxy (td, J =7.0, 2.0 Hz, 3 H), 1.34-1.88 (m, 15 H), 1.99-2.07 at 7.33 min, UV activeethanimidoyl]piperidin-1- (m, 1 H), 2.13-2.22 (m, 2 H), 2.34-2.43 (m, 1H), 2.68- yl}azepane-1-carboxylate 2.79 (m, 2 H), 3.16-3.25 (m, 2 H),3.41-3.46 (m, 2 H), 3.88 (t, J = 6.5 Hz, 2 H), 4.03 (qd, J = 7.0, 2.5Hz, 2 H) 1-9 Isomer 1 (racemic): Ethyl 1 and 25 a 400 MHz, (DMSO-d₆) δ:1.13-1.19 (m, 9 H), 1.30-1.63 E m/z 354 (M + H)⁺ (ES⁺)4-{4-[N-(propan-2- (m, 7 H), 1.71-1.89 (m, 6 H), 2.08-2.29 (m, 2 H),2.34- at 6.91 min, UV active yloxy)ethanimidoyl] 2.45 (m, 1 H),2.68-2.89 (m, 3 H), 3.16-3.24 (m, 2 H), piperidin-1-yl}azepane-1-3.41-3.45 (m, 2 H), 4.03 (qd, J = 7.0, 2.5 Hz, 2 H), 4.10- carboxylate4.19 (m, 1 H) 1-9 Isomer 2 (racemic): Ethyl 1 and 25 a 400 MHz,(DMSO-d₆) δ: 1.14-1.19 (m, 9 H), 1.29-1.86 E m/z 354 (M + H)⁺ (ES⁺)4-{4-[N-(propan-2- (m, 13 H), 2.00-2.22 (m, 3 H), 2.34-2.44 (m, 1 H),2.67- at 7.40 min, UV active yloxy)ethanimidoyl] 2.82 (m, 2 H),3.16-3.25 (m, 2 H), 3.39-3.51 (m, 2 H), piperidin-n-1-yl}azepane- 4.03(qd, J = 7.0, 2.5 Hz, 2 H), 4.12-4.21 (m, 1 H) 1-carboxylate 1-10 Isomer1 (racemic): Ethyl 3 and 23 a 400 MHz, (DMSO-d₆) δ: 0.99 (t, J = 7.5 Hz,3 H), 1.14- E m/z 354 (M + H)⁺ (ES⁺) 4-{4-[N-ethoxy 1.19 (m, 6 H),1.24-1.60 (m, 7 H), 1.71-1.86 (m, 3 H), at 7.46 min, UV activepropanimidoyl]pipendin-1- 2.11-2.23 (m, 4 H), 2.34-2.41 (m, 1 H),2.66-2.90 (m, yl}azepane-1-carboxylate 3 H), 3.13-3.27 (m, 2 H),3.39-3.50 (m, 2 H), 3.94- 4.05 (m, 4 H) 1-10 Isomer 2 (racemic): Ethyl 3and 23 a 400 MHz, (DMSO-d₆) δ: 0.98 (t, J = 7.5 Hz, 3 H), 1.14- E m/z354 (M + H)⁺ (ES⁺) 4-{4-[N-ethoxy 1.19 (m, 6 H), 1.24-1.85 (m, 10 H),2.00-2.21 (m, 5 H), at 7.63 min, UV active propanimidoyl]piperidin-1-2.34-2.42 (m, 1 H), 2.68-2.82 (m, 2 H), 3.16-3.25 (m,yl}azepane-1-carboxylate 2 H), 3.39-3.51 (m, 2 H), 3.93-4.05 (m, 4 H)1-11 Isomer 1 (racemic): Ethyl 3 and 24 a 400 MHz, (DMSO-d₆) δ: 0.87 (t,J = 7.5 Hz, 3 H), 0.99 E m/z 368 (M + H)⁺ (ES⁺) 4-{4-[N-propoxy (t, J =7.5 Hz, 3 H), 1.15-1.19 (m, 3 H), 1.24-1.61 (m, 9 at 8.16 min, UV activepropanimidoyl]piperidin-1- H), 1.70-1.86 (m, 3 H), 2.08-2.24 (m, 4 H),2.33-2.44 yl}azepane-1-carboxylate (m, 1 H), 2.65-2.90 (m, 3 H),3.14-3.27 (m, 2 H), 3.41- 3.53 (m, 2 H), 3.88 (t, J = 6.5 Hz, 2 H),4.0-4.05 (m, 2 H) 1-11 Isomer 2 (racemic): Ethyl 3 and 24 a 400 MHz,(DMSO-d₆) δ: 0.88 (t, J = 7.5 Hz, 3 H), 0.99 E m/z 368 (M + H)⁺ (ES⁺)4-{4-[N-propoxy (t, J = 7.5 Hz, 3 H), 1.16-1.19 (m, 3 H), 1.24-1.90 (m,12 at 8.34 min, UV active propanimidoyl]piperidin-1- H), 2.00-2.29 (m, 4H), 2.34-2.43 (m, 1 H), 2.59-2.86 yl}azepane-1-carboxylate (m, 3 H),3.16-3.25 (m, 2 H), 3.41-3.47 (m, 2 H), 3.87 (t, J = 6.5 Hz, 2 H),3.99-4.14 (m, 2 H) 1-12 Isomer 1 (racemic): Ethyl 3 and 25 a 400 MHz,(DMSO-d₆) δ: 0.99 (t, J = 7.5 Hz, 3 H), 1.14- E m/z 368 (M + H)⁺ (ES⁺)4-{4-[N-(propan-2- 1.83 (m, 20 H), 2.11-2.27 (m, 4 H), 2.34-2.42 (m, 1H), at 8.25 min, UV active yloxy)propanimidoyl] 2.68-2.89 (m, 2 H),3.17-3.27 (m, 2 H), 3.41-3.51 (m, piperidin-1-yl}azepane-1- 2 H), 4.03(qd, J = 7.0, 2.0 Hz, 2 H), 4.12-4.22 (m, 1 H) carboxylate 1-12 Isomer 2(racemic): Ethyl 3 and 25 a 400 MHz, (DMSO-d₆) δ: 0.98 (t, J = 7.5 Hz, 3H), 1.14- E m/z 368 (M + H)⁺ (ES⁺) 4-{4-[N-(propan-2- 1.92 (m, 19 H),2.01-2.25 (m, 5 H), 2.32-2.46 (m, 1 H), at 8.48 min, UV activeyloxy)propanimidoyl] 2.66-2.80 (m, 2 H), 3.16-3.25 (m, 2 H), 3.41-3.54(m, piperidin-1-yl}azepane-1- 2 H), 4.03 (qd, J = 7.0, 2.0 Hz, 2 H),4.11-4.20 (m, 1 H) carboxylate 2-1 Mixture of isomers 1: Ethyl 16 a 400MHz, (MeOD-d₄) δ: 1.25-1.30 (m, 3 H), 1.57-2.28 D m/z 338 (M + H)⁺ (ES⁺)2-{4-[N-methoxy (m, 17 H), 2.82-3.11 (m, 4 H), 3.36-3.44 (m, 2 H), 3.78-at 6.22 min, UV active ethanimidoyl]piperidin-1- 3.80 (m, 3 H),4.09-4.16 (m, 2 H) yl}-6-azaspiro[3.4]octane- 6-carboxylate 2-1 Mixtureof isomers 2: Ethyl 16 a 400 MHz, (MeOD-d₄) δ: 1.27 (t, J = 7.0 Hz, 3H), 1.61- D m/z 338 (M + H)⁺ (ES⁺) 2-{4-[N-methoxy 1.71 (m, 2 H),1.79-1.84 (m, 5 H), 1.93-2.06 (m, 7 H), at 6.40 min, UV activeethanimidoyl]piperidin-1- 2.14-2.26 (m, 3 H), 2.78-3.08 (m, 3 H), 3.29(s, 1 H), yl}-6-azaspiro[3.4]octane- 3.41 (q, J = 7.0 Hz, 2 H), 3.80 (s,3 H), 4.11 (q, J = 7.0 6-carboxylate Hz, 2 H) 2-2 Isomer 1: Ethyl2-{4-[N- 18 a 400 MHz, (MeOD-d₄) δ: 1.11 (t, J = 7.5 Hz, 3 H), 1.25- Dm/z 352 (M + H)⁺ (ES⁺) methoxypropanimidoyl] 1.30 (m, 3 H), 1.69-1.76(m, 2 H), 1.87-1.99 (m, 8 H), at 6.72 min, UV active piperidin-1-yl}-6-2.13-2.25 (m, 5 H), 2.81-3.07 (m, 3 H), 3.37-3.40 (m,azaspiro[3.4]octane-6- 4 H), 3.79 (s, 3 H), 4.10-4.15 (m, 2 H)carboxylate 2-2 Isomer 2: Ethyl 2-{4-[N- 18 a 400 MHz, (MeOD-d₄) δ: 1.07(t, J = 7.5 Hz, 3 H), 1.26- D m/z 352 (M + H)⁺ (ES⁺)methoxypropanimidoyl] 1.31 (m, 3 H), 1.65-2.33 (m, 15 H), 2.91-3.12 (m,3 H), at 6.82 min, UV active piperidin-1-yl}-6- 3.36-3.41 (m, 4 H), 3.79(s, 3 H), 4.13 (q, J = 7.0 Hz, 2 azaspiro[3.4]octane-6- H) carboxylate2-2 Isomer 3: Ethyl 2-{4-[N- 18 a 400 MHz, (MeOD-d₄) δ: 1.11 (t, J = 7.5Hz, 3 H), 1.25- D m/z 352 (M + H)⁺ (ES⁺) methoxypropanimidoyl] 1.28 (m,3 H), 1.65-1.71 (m, 2 H), 1.80-2.01 (m, 8 H), at 6.91 min, UV activepiperidin-1-yl}-6- 2.06-2.32 (m, 5 H), 2.76-2.80 (m, 1 H), 2.96-3.01 (m,azaspiro[3.4]octane-6- 2 H), 3.28-3.45 (m, 4 H), 3.79 (s, 3 H),4.09-4.14 (m, 2 carboxylate H) 2-2 Isomer 4: Ethyl 2-{4-[N- 18 a 400MHz, (MeOD-d₄) δ: 1.07 (t, J = 7.5 Hz, 3 H), 1.25- D m/z 352 (M + H)⁺(ES⁺) methoxypropanimidoyl] 1.31 (m, 3 H), 1.61-2.32 (m, 15 H),2.79-2.92 (m, 1 H), at 7.01 min, UV active piperidin-1-yl}-6- 2.99-3.01(m, 2 H), 3.29-3.44 (m, 4 H), 3.79 (s, 3 H), azaspiro[3.4]octane-6- 4.11(q, J = 7.0 Hz, 2H) carboxylate 2-3 Isomer 1: Ethyl 2-{4-[N- 19 a 400MHz, (MeOD-d₄) δ: 0.97 (t, J = 7.5 Hz, 3 H), 1.28 D m/z 366 (M + H)⁺(ES⁺) methoxybutanimidoyl] (td, J = 7.0, 2.5 Hz, 3 H), 1.54-1.63 (m, 3H), 1.69-1.73 at 7.42 min, UV active piperidin-1-yl}-6- (m, 4H),1.84-1.95 (m, 6 H), 2.14-2.18 (m, 4 H), 2.74- azaspiro[3.4]octane-6-2.87 (m, 1 H), 2.95-3.04 (m, 2 H), 3.35-3.40 (m, 4 H), carboxylate 3.79(s, 3 H), 4.13 (q, J = 7.0 Hz, 2 H) 2-3 Mixture of two isomers: 19 a 400MHz, (MeOD-d₄) δ: 0.91-0.99 (m, 3 H), 1.25-1.29 D m/z 366 (M + H)⁺ (ES⁺)Ethyl 2-{4-[N- (m, 3 H), 1.48-1.98 (m, 12 H), 2.10-2.27 (m, 5 H), 2.74-at 7.60 min, UV active methoxybutanimidoyl] 2.84 (m, 1 H), 2.96-2.99 (m,2 H), 3.28-3.43 (m, 4 H), piperidin-1-yl}-6- 3.78 (m, 3 H), 4.09-4.15(m, 2 H) azaspiro[3.4]octane-6- carboxylate 2-3 Isomer 4: Ethyl 2-{4-[N-19 a 400 MHz, (MeOD-d₄) δ: 0.95 (t, J = 7.5 Hz, 3 H), 1.27 D m/z 366(M + H)⁺ (ES⁺) methoxybutanimidoyl] (t, J = 7.0 Hz, 3 H), 1.48-1.58 (m,2 H), 1.64-1.73 (m, 3 at 7.70 min, UV active piperidin-1-yl}-6- H),1.85-1.89 (m, 2 H), 1.94-2.28 (m, 10 H), 2.92-3.18azaspiro[3.4]octane-6- (m, 3 H), 3.31 (s, 2 H), 3.42 (q, J = 7.0 Hz, 2H), 3.78 (s, carboxylate 3 H), 4.12 (q, J = 7.0 Hz, 2 H) 3-1 Mixture ofisomers: Ethyl 21 b 400 MHz, (DMSO-d₆) δ: 0.85 (d, J = 6.5 Hz, 6 H),1.16- C m/z 383 (M + H)⁺ (ES⁺) 4-{4-[N′-methoxy-N-(2- 1.24 (m, 8 H),1.35-2.06 (m, 11 H), 2.83 (t, J = 6.5 Hz, 2 at 1.78 min, UV activemethylpropyl) H), 3.18-3.30 (m, 2 H), 3.43-3.51 (m, 3 H), 3.59 (s, 3carbamimidoyl]piperidin- H), 4.02-4.06 (m, 2 H), 5.42 (s, 1 H)1-yl}azepane-1- carboxylate 4-1 Mixture of isomers: Ethyl 21 c 400 MHz,(DMSO-d₆) δ: 1.17 (td, J = 7.0, 1.5 Hz, 3 H), B m/z 365 (M + H)⁺ (ES⁺)4-(4-{cyano[(propan-2- 1.25 (d, J = 6.5 Hz, 6 H), 1.35-1.81 (m, 10 H),2.15- at 4.70 min, UV active yloxy)imino]methyl} 2.47 (m, 4 H),2.71-2.83 (m, 2 H), 3.16-3.25 (m, 2 H), piperidin-1-yl)azepane-1-3.38-3.49 (m, 2 H), 4.03 (qd, J = 7.0, 1.5 Hz, 2 H), 4.42- carboxylate4.53 (m, 1 H)

Biological Activity Example A Phospho-ERK1/2 Assays

Functional assays were performed using the Alphascreen Surefirephospho-ERK1/2 assay (Crouch & Osmond, Comb. Chem. High ThroughputScreen, 2008). ERK1/2 phosphorylation is a downstream consequence ofboth Gq/11 and Gi/o protein coupled receptor activation, making ithighly suitable for the assessment of M₁, M₃ (Gq/11 coupled) and M₂, M₄receptors (Gi/o coupled), rather than using different assay formats fordifferent receptor subtypes. CHO cells stably expressing the humanmuscarinic M₁, M₂, M₃ or M₄ receptor were plated (25K/well) onto 96-welltissue culture plates in MEM-alpha +10% dialysed FBS. Once adhered,cells were serum-starved overnight. Agonist stimulation was performed bythe addition of 5 μL agonist to the cells for 5 min (37° C.). Media wasremoved and 50 μL of lysis buffer added. After 15 min, a 4 μL sample wastransferred to 384-well plate and 7 μL of detection mixture added.Plates were incubated for 2 h with gentle agitation in the dark and thenread on a PHERAstar plate reader.

pEC₅₀ and E_(max) figures were calculated from the resulting data foreach receptor subtype.

For all examples cis and trans oxime isomers exist and have beenseparated, unless stated otherwise, absolute configuration has not beendefined and assignment of different isomers based on their retentiontime on LCMS analytical trace has been performed. When racemic startingmaterials are used then the separated isomers are still racemicmixtures. For some examples two additional diastereomers exist acrossthe cyclobutane ring; when possible these have been separated, unlessstated otherwise, and assigned based on their retention time on LCMSanalytical trace.

Analytical data for active isomers is reported in Table 3. Data forseveral weakly active compounds are also included in Table 4 tohighlight a preference of absolute stereochemistry.

The results are set out in Table 4 below.

TABLE 4 Muscarinic Activity pEC₅₀ M₁ pEC₅₀ M₂ PEC₅₀ M₃ pEC₅₀ M₄ (% Emaxcf. (% Emax cf. (% Emax cf. (% Emax cf. Ex. No. ACh) ACh) ACh) ACh) ACh  8.3 (102)   7.8 (105)   8.1 (115)   8.1 (110) 1-1 Isomer 2 (racemic)  5.8 (54) <4.7 (4) <4.7 (1)   6.9 (71) (S)-1-1 Isomer 1   6.2 (47) NTNT   6.7 (31) (S)-1-1 Isomer 2   6.3 (49) <4.7 (7) <4.7 (0)   6.7 (62)1-2 Isomer 1 (racemic)   6.3 (58) <4.7 (2) <4.7 (37)   7.1 (99) 1-2Isomer 2 (racemic)   6.4 (83) <4.7 (7) <4.7 (1)   7.6 (94) (S)-1-2Isomer 1 <4.7 (21) <4.7 (11) <4.7 (9)   7.2 (81) (S)-1-2 Isomer 2   6.3(36) <4.7 (5) <4.7 (7)   7.3 (81) 1-3 Isomer 1 (racemic)   6.5 (106) NTNT   7.6 (85) 1-3 Isomer 2 (racemic)   7.2 (92) <4.7 (21) <4.7 (17)  7.3 (83) (S)-1-3 Isomer 2   6.6 (93) <4.7 (7) <4.7 (0)   7.6 (126) 1-4Isomer 1 (racemic)   6.4 (87) <4.7 (24) <4.7 (5)   7.3 (115) 1-4 Isomer2 (racemic)   6.5 (95) <4.8 (7) <4.8 (6)   7.5 (107) 1-5 Isomer 2(racemic)   6.5 (105) <4.7 (22) <4.7 (4)   7.5 (104) 1-6 Isomer 2(racemic)   7.4 (96) <4.7 (10) <4.7 (16)   6.9 (65) 1-7 Isomer 1(racemic)   6.2 (48) NT NT   6.2 (52) 1-7 Isomer 2 (racemic)   6.3 (66)NT NT   6.6 (62) 1-8 Isomer 1 (racemic)   6.1 (65) NT NT   6.1 (46) 1-8Isomer 2 (racemic)   6.5 (85) NT NT   6.5 (50) 1-9 Isomer 1 (racemic)  6.2 (57) NT NT <4.7 (0) 1-9 Isomer 2 (racemic)   6.2 (46) NT NT   6.4(81) 1-10 Isomer 1 (racemic)   6.3 (58) NT NT   7.0 (89) 1-11 Isomer 1(racemic)   6.6 (107) NT NT   6.9 (72) 1-11 Isomer 2 (racemic)   6.8(99) <4.7 (19) <4.7 (6)   7.2 (97) 1-12 Isomer 1 (racemic)   7.0 (98)<4.7 (5) <4.7 (6)   7.2 (80) 1-12 Isomer 2 (racemic)   6.5 (72) <4.7 (2)<4.7 (1)   7.6 (101) 2-1 Mixture of isomers 2   6.7 (89) <4.7 (71) <4.7(9)   7.2 (68) 2-2 Isomer 3 <4.7 (5) <4.7 (7) <4.7 (2)   7.3 (67) 2-2Isomer 4   6.7 (59) <4.7 (69) <4.7 (18)   7.7 (105) 2-3 Mixture of twoisomers <4.7 (22) <4.7 (7) <4.7 (5)   7.7 (93) 2-3 Isomer 4   6.8 (87)<4.7 (15) <4.7 (7)   7.6 (77) 3-1 Mixture of isomers   6.6 (136) NT NT  6.4 (56) 4-1 Mixture of isomers   7.0 (109) <4.7 (4) <4.7 (5)   7.1(72)

Example B Pharmaceutical Formulations (i) Tablet Formulation

A tablet composition containing a compound of the formula (1) isprepared by mixing 50 mg of the compound with 197 mg of lactose (BP) asdiluent, and 3 mg magnesium stearate as a lubricant and compressing toform a tablet in known manner.

(ii) Capsule Formulation

A capsule formulation is prepared by mixing 100 mg of a compound of theformula (1) with 100 mg lactose and optionally 1% by weight of magnesiumstearate and filling the resulting mixture into standard opaque hardgelatin capsules.

Equivalents

The foregoing examples are presented for the purpose of illustrating theinvention and should not be construed as imposing any limitation on thescope of the invention. It will readily be apparent that numerousmodifications and alterations may be made to the specific embodiments ofthe invention described above and illustrated in the examples withoutdeparting from the principles underlying the invention. All suchmodifications and alterations are intended to be embraced by thisapplication.

1. A compound of formula (1):

or a salt thereof, wherein: p is 0; q is 0; Y is N, O, S or C; X¹ and X²are saturated hydrocarbon groups which together contain a total of fourto nine carbon atoms and which link together such that the moiety:

forms a mono or bicyclic ring system; R¹ is selected from methyl, ethyl,propyl, and isopropyl; R² is selected from cyano, methyl, ethyl, propyl,isopropyl, butyl, and isobutyl; R³ is selected from hydrogen, fluorine,and methoxy; R⁴ is selected from hydrogen, methyl, ethyl, ethynyl, and1-propynyl; R⁵ is fluorine; and R⁶ is fluorine. 2-7. (canceled)
 8. Thecompound according to claim 1, or a salt thereof, wherein the bicyclicring system formed by the moiety:

is selected from: (a) piperidine; (b) azepane; (c) an azabicyclo-octaneor azabicyclo-nonane ring system; (d) 2-aza-spiro[3.4]octane or a6-aza-spiro[3.4]octane ring system; and (e) a cyclopentanopyrrolidinering system,.
 9. The compound according to claim 2, or a salt thereof,wherein the bicyclic ring system formed by the moiety:

is selected from ring systems below:


10. The compound according to claim having the formula (2):

or a salt thereof, s is 0 or 1 and t is 0 or
 1. 11. A compound,.according to claim 1 which is selected from: Ethyl4-{4-[N-methoxyethanimidoyl]piperidin-1-yl}azepane-1-carboxylate; Ethyl(4 S)-4-{4-[N-methoxyethanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl 4-{4-[N-methoxypropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl(4S)-4-{4-[N-methoxypropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl 4-{4-[N-methoxybutanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl(4S)-4-{4-[N-methoxybutanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl4-{4-[N-methoxy-2-methylpropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl4-{4-[N-methoxy-2-methylpropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl 4-{4-[N-methoxy-4-methylpentanimidoyl]piperidin-1-yl}azepane-1-carboxylate; Ethyl4-{4-[N-ethoxyethanimidoyl]piperidin-1-yl}azepane-1-carboxylate; Ethyl4-{4-[N-propoxyethanimidoyl]piperidin-1-yl}azepane-1-carboxylate; Ethyl4-{4-[N-(propan-2-yloxy)ethanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl 4-{4-[N-ethoxypropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl 4-{4-[N-propoxypropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl4-{4-[N-(propan-2-yloxy)propanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl2-{4-[N-methoxyethanimidoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[N-methoxypropanimidoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[N-methoxybutanimidoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl4-{4-[N′-methoxy-N-(2-methylpropyl)carbamimidoyl]piperidin-1-yl}azepane-1-carboxylate;and Ethyl4-(4-{cyano[(propan-2-yloxy)imino]methyl}piperidin-1-yl)azepane-1-carboxylate;or a salt thereof. 12-14. (canceled)
 15. A pharmaceutical compositioncomprising a compound according to claim 1, or a salt thereof, and apharmaceutically acceptable excipient. 16-18. (canceled)
 19. A compound,which is selected from: Ethyl 4-{4-[N-methoxypropanimidoyl]piperidin-1-yl}azepane-1-carboxylate; Ethyl4-{4-[N-methoxybutanimidoyl]piperidin-1-yl}azepane-1-carboxylate; Ethyl4-{4-[N-methoxy-2-methylpropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl4-{4-[N-methoxy-2-methylpropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl4-{4-[N-(propan-2-yloxy)propanimidoyl]piperidin-1-yl}azepane-1-carboxylate;Ethyl2-{4-[N-methoxypropanimidoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;and Ethyl2-{4-[N-methoxybutanimidoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,or a salt thereof.
 20. A method of treating a subject suffering fromAlzheimer's Disease, an acute, chronic, neuropathic, or inflammatorypain, comprising administering to the subject an effective amount of acompound according to claim 1, or a salt thereof, that exhibitsselectivity for the M₁ and M4 receptor relative to the M₂ and M₃receptor subtypes.
 21. A method of treating a subject suffering fromschizophrenia, comprising administering to the subject an effectiveamount of a compound according to claim 1, or a salt thereof, thatexhibits selectivity for the M4 receptor relative to the M₁, M₂ and M₃receptor subtypes.